Immunology Letters 253 (2023) 19–27

Available online 29 December 2022
0165-2478/© 2022 The Author(s). Published by Elsevier B.V. on behalf of European Federation of Immunological Societies. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Review 

Dendritic cells in energy balance regulation 

Ana Redondo-Urzainqui 1, Elena Hernández-García 1, Emma Clare Laura Cook *,2, 
Salvador Iborra ** 

Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, Madrid, 28040, Spain   

A R T I C L E  I N F O   

Keywords: 
Obesity 
Dendritic cells 
Adipose tissue 
Homeostasis 
Flt3l, cDC1 

A B S T R A C T   

Besides their well-known role in initiating adaptive immune responses, several groups have studied the role of 
dendritic cells (DCs) in the context of chronic metabolic inflammation, such as in diet-induced obesity (DIO) or 
metabolic-associated fatty liver disease. DCs also have an important function in maintaining metabolic tissue 
homeostasis in steady-state conditions. In this review, we will briefly describe the different DC subsets, the 
murine models available to assess their function, and discuss the role of DCs in regulating energy balance and 
maintaining tissue homeostasis.   

1. Introduction to DCs 

DCs are antigen-presenting cells critical for triggering immunity to 
infections or cancer, but also for maintaining tolerance during homeo-
stasis [1]. To accomplish these functions, DCs detect infected, stressed, 
or damaged cells through pattern recognition receptors that sense 
pathogen-associated molecular patterns [2,3], or damage-associated 
molecular patterns and convey these stimuli to naïve T cells, linking 
innate and adaptive immunity. DCs efficiently capture antigens and, 
during their migration to regional lymph nodes (LNs) or other T lym-
phocytes zones, process them into peptides bound to major histocom-
patibility complexes (MHC). The migration via afferent lymphatic 
vessels to the draining LNs is enabled by the upregulation of the 
chemotactic receptor (CCR)7 that allows activated DCs to sense a hap-
totactic gradient of C–C Motif Chemokine Ligand (CCL) 21 and CCL19 
generated by lymphatic endothelial cells [4,5]. Induction of adaptive 
immunity or tolerance depends on the signals received by the DCs that 
are further conveyed to naïve T cells during antigen presentation [4]. 
DCs can also contribute to eliminate autoreactive T cells during central 
immune tolerance in the thymus, and are critical to maintain peripheral 
tolerance, preventing autoimmunity and tissue damage [5]. 

1.1. Ontogeny, classification and function in host defense 

DCs are a heterogeneous population exhibiting different surface 
markers, localization and function. Conventional DCs (cDCs) and plas-
macytoid DCs (pDCs) arise from a diverse array of progenitors in the 
bone marrow (BM) derived from hematopoietic stem cells that can give 
rise to common myeloid progenitors (CMPs). CMPs further differentiate 
into macrophage/DC progenitors (MDPs), which in turn differentiate 
into common DC progenitors (CDPs) or common monocyte precursors 
(cMOPs) [1]. cMOPs lack the tyrosine kinase receptor Flt3 and differ-
entiate into monocytes, which can differentiate into inflammatory DCs 
(moDCs) in peripheral tissues. CDPs do not exit the BM and retain 
CD115 and Flt3 expression. Its ligand (Flt3L) regulates cDC and pDC 
development in the steady state. CDPs give rise to pre-DCs, which 
migrate through the blood to lymphoid and non-lymphoid organs, 
where they differentiate into cDCs or pDCs. Other studies have shown 
DC-committed cells among lymphoid-primed multipotent progenitors 
[4]. cDCs can be found in the T cell zone of the LN and the spleen and the 
thymus medulla, as well as in non-lymphoid organs [6–8]. Different cDC 
subtypes exist that express different surface markers (see next section) 
and perform different functions. Type 1 cDCs (cDC1) are characterized 

* Corresponding author. 
** Corresponding author. 

E-mail addresses: eccook@cnic.es (E.C.L. Cook), siborra@ucm.es (S. Iborra).   
1 Contributed equally  
2 Current address: Centro Nacional de Investigaciones Cardiovasculares, Madrid, 28029, Spain 

Contents lists available at ScienceDirect 

Immunology Letters 

journal homepage: www.elsevier.com/locate/immlet 

https://doi.org/10.1016/j.imlet.2022.12.002 
Received 30 October 2022; Received in revised form 21 December 2022; Accepted 26 December 2022   

mailto:eccook@cnic.es
mailto:siborra@ucm.es
www.sciencedirect.com/science/journal/01652478
https://www.elsevier.com/locate/immlet
https://doi.org/10.1016/j.imlet.2022.12.002
https://doi.org/10.1016/j.imlet.2022.12.002
https://doi.org/10.1016/j.imlet.2022.12.002
http://crossmark.crossref.org/dialog/?doi=10.1016/j.imlet.2022.12.002&domain=pdf
http://creativecommons.org/licenses/by-nc-nd/4.0/


Immunology Letters 253 (2023) 19–27

20

by the expression of the C-type lectin receptor Clec9a (also known as 
DNGR-1), and the X-C motif chemokine receptor 1 (XCR1). cDC1s are 
specialized in processing exogenous antigen for cross-presentation via 
MHC-I to CD8 T cells [9–11]. Through the production of interleukin 
(IL)− 12, they promote T helper type 1 (Th1) and NK cell responses, 
contributing also to the priming of tissue-resident memory CD8+ T cells 
[12]. Secretion of Chemokine (C motif) ligand 1 (XCL1), the unique 
known ligand for XCR1, by memory T cells, NK cells (NKs) [13] and 
invariant natural killer T cells (iNKTs) [14] allow their interaction with 
cDC1s. cDC1s seem to play an essential role in promoting antitumor 
immunity [15–17]. Mice deficient in cDC1s exhibit impaired antigen 
cross-presentation, cytotoxic lymphocyte responses against viral infec-
tion, and responses to tumor challenges [16]. cDC2s are more abundant 
and heterogeneous than cDC1s, and mediate antigen presentation via 
MHC-II to CD4+ T cells, promoting their differentiation into T helper 

type 17 (Th17) and 2 (Th2) [7,10,11,18–20]. It has been suggested that 
cDC2s can be further classified into cDC2As and cDC2Bs depending on 
the expression of T-bet and RORγt, respectively [21]. Although both 
subsets share transcriptional and functional characteristics, cDC2As 
express amphiregulin, a molecule linked to tissue repair, and have an 
anti-inflammatory function, whereas cDC2Bs play a pro-inflammatory 
function [21]. pDCs recognize intracellular viral or self-DNA and RNA 
via Toll-like receptors (TLRs) and produce high quantities of type I and 
III interferons (IFNs) [22]. They play essential roles in the antiviral 
response and the initiation and development of many autoimmune and 
inflammatory diseases [1–4]. pDCs have been thought to also be able to 
cross-prime CD8+ T cells and present antigens to CD4+ T cells through 
secretion of pro-inflammatory cytokines and chemokines and expression 
of co-stimulatory or co-inhibitory molecules [23,24]. However, recent 
data suggest that a preDC subset expressing similar markers to pDCs 

Fig. 1. Dendritic cell markers and murine models for targeting and depletion of different subsets. (A) Markers in mice (upper panel) and humans (lower panel), 
together with their characteristic transcription factors (middle panel) for each dendritic cell subset. (B) Mouse models for targeting DCs. Above the dashed line: DC 
subsets targeted by the different Cre “drivers”, bellow the dashed lines, other populations impacted by the Cre. Right panel, combination of this Cre mice with floxed 
STOP cassettes, followed by genes encoding either the diptheria toxin A (DTA), or its human receptor (hDTR), allows the constitutive or conditional deletion of the 
targeted populations, respectively. (C) Murine models deficient for specific DC subpopulations (above the dashed lines), other cells deleted or impacted by the genetic 
modification are shown below the dashed lines *cDC2s are targeted/deleted only in homozygous transgenic animals. 

A. Redondo-Urzainqui et al.                                                                                                                                                                                                                  



Immunology Letters 253 (2023) 19–27

21

(CD123, CD303, and CD304) is actually responsible for the T cell acti-
vation ability [25,26]. This poses the question whether pDCs are 
adequately classified as antigen-presenting cells since they are not effi-
cient antigen presenters or processors and their main route of migration 
into lymph nodes is directly from the blood [27]. 

Monocytes recruited to injury sites during the onset of inflammation 
can develop into moDCs. Scarce or even absent under homeostatic 
conditions [28], their differentiation is promoted not only during viral, 
bacterial, fungal, and protozoan infections, but also in autoimmune and 
allergic disorders. Although moDCs are known to induce Th1 and Th17 
responses, they can also promote Th2 responses and cross-present 
exogenous antigen to CD8+ T cells under certain stimuli [29]. 

1.2. Markers and lineage-specification transcription factors 

This section will focus on markers and lineage-specification tran-
scription factors of different DC subsets in mouse. Markers expressed by 
their human homologues are shown in the lower panel of Fig. 1A [23,30, 
31]. cDC1s are identified by the surface expression of MHCII, CD11c 
(Itgax), XCR1, Clec9a (DNGR-1), CD24 CD205 (DEC205), CD207 (Lan-
gerin), and CD8α for resident cells. CD103 (Itgae) is a marker for 
migratory cDC1 in most tissues, but in the intestine, both CD103+ cDC1s 
and cDC2s are present and mediate pro-tolerogenic responses [32–36]. 
However, only Clec9a and XCR1 are exclusively expressed by this subset 
(Fig. 1A, upper panel). Clec9a recognizes and mediates the antigenic 
processing of damaged cells [37,38], whereas XCR1 allows the crosstalk 
with cells secreting XCL1, such as NK cells or CD8 T cells. cDC1s show 
lower expression of CD11b (Itgam) and SIRPα (CD172a) than cDC2s, but 
higher amounts of Flt3 [4,39]. Expression of the transcription factors 
Batf3, interferon regulatory factor (Irf) 8, Nfil3 (E4BP4) and Id2 dis-
tinguishes cDC1s from other subtypes, and are required for their 
development (Fig. 1A, middle panel). cDC2s express MHCII, CD11c, 
CD11b and SIRPα (Fig. 1A, upper panel) [1]. In most tissues, cDC2s do 
not express CD103, except in the intestine [39,40]. cDC2s specifically 
express the transcription factors Irf4, Irf2, and the adapter protein Traf6 
(Fig. 1A, middle panel), which are required for their development and 
function [1,5]. Some cDC2 subsets in spleen, lung and gut-associated 
lymphoid tissues depend on Notch2, while a Klf4-dependent subset in-
cludes migratory cDC2s (reviewed by [41]). Murine pDCs express 
MHCII, Siglec-H, B220, Ly-6C, PDCA1 (CD317) and intermediate CD11c 
(Fig. 1A, upper panel). pDCs are characterized by the expression of Irf8, 
E2–2 (TCF-4) and Irf7 transcription factors (Fig. 1A, middle panel). 
moDCs express MHCII, CD11b, CD11c, CD209 (DC-Sign), Ly-6 G, Ly-6C, 
CD206 (MMR), CD64 (FcgRI), F4/80 (Adgre1), SIRPα, and CD14 
(Fig. 1A, upper panel). The transcription factor NR4A3 guides their 
differentiation to moDCs (Fig. 1A, middle panel) [42]. 

DC maturation is defined by increased surface expression of MHC 
molecules and costimulatory molecules as CD80, CD86, and CD40, as 
well as upregulation of the chemokine receptor CCR7. However, cDCs 
can instruct differentiation to Th1, Th2, and Th17 cells and also to Tregs, 
so the term maturation has been changed to activation [40]. 

1.3. Mouse models for analysis of specific DC functions and for their 
depletion 

CD11cCre transgenic mice [43] allow the deletion of floxed gene se-
quences in pDCs, cDCs and moDCs (Fig. 1B). This is an important mouse 
model for studying DC homeostasis and DC-specific function. However, 
this Cre “driver” does not exclusively target DCs, but other 
CD11c-expressing cells, such as certain subtypes of macrophages and B 
cells. Flt3 expression is preserved in terminally differentiated cDCs and 
pDCs and the administration of Flt3L promotes the expansion of both 
populations [44–46]. Consequently, Flt3L− /− mice have decreased 

numbers of cDCs and pDCs in both lymphoid and peripheral tissues [44, 
46]. However, these mice also have a defect in other immune pop-
ulations (view Fig. 1). cDCs differ from other DC populations by the 
expression of the transcription factor Zinc Finger and BTB Domain 
Containing 46 (Zbtb46) that is also expressed by committed erythroid 
progenitors and endothelial cell populations. Thus, the Zbtb46Cre 

transgenic mice [47] allows the specific deletion of floxed sequences in 
cDCs (Fig. 1B), but it also targets other non-immune cells (view Fig. 1) 
[48]. 

XCR1cre and Clec9acre can be considered as specifically targeting 
cDC1s. However, since Clec9a is expressed during the ontogeny of 
cDC2s, this population is also targeted, particularly in mice homozygous 
for the transgene [49]. Selective targeting of pDCs can be achieved by 
using a Clec4c (Bdca2)Cre transgenic mouse [50–53]. Batf3− /− mice 
either harbor reduced number of non-functional cells or no CD103+

cDC1s in non-lymphoid tissues, depending on the mouse strain (Fig. 1B) 
[54]. Notwithstanding, Batf3 plays an intrinsic role in other immune 
cells, such as memory T cells [55]. For constitutive or conditional 
depletion of the different DC subsets, the aforementioned Cre “drivers” 
can be combined with floxed STOP cassettes, followed by genes 
encoding either the diptheria toxin A (DTA), or its human receptor 
(hDTR) respectively (Fig. 1C). cDC1s, but no other DC subsets express 
the Karma gene, which encodes a protein likely corresponding to a G 
protein-coupled receptor (Gpr141b). A Karma knock-in reporter/deleter 
mouse model, expressing a construct encoding both a fluorescent re-
porter and hDTR in the Karma locus, allows specific tracking and con-
ditional depletion of cDC1s in vivo, although mast cells express similar 
levels of the Karma gene as cDC1s [56]. 

Up until very recently, there were no satisfactory models for the 
depletion of the entire cDC2 subset. However, a new model uses the 
competition between Nfil3 and C/EBP for Zeb2 enhancer sites. A tran-
sient binding of Nfil3 to these enhancer sites is required for CDP dif-
ferentiation into cDC1s. If this binding is abrogated, CDPs are committed 
to the pre-cDC2 lineage. This model will open up the field for the study 
of cDC2 functionality. An initial study in the same article showed a 
reliance of Th2 responses in helminth infections on cDC2s [57]. 

Deletion of the transcription factor NR4A3 allows the depletion of 
MoDCs. However, it also has an impact on hematopoietic stem cells 
[42]. Alternatively, blocking monocyte infiltration through neutraliza-
tion of the chemokine CCL2 or its receptor, as well as inhibiting of 
colony-stimulating factor-1 receptor signaling prevented the generation 
of moDCs, but these treatments also affect monocyte-derived macro-
phages [58]. 

In essence, deleting specific subpopulations of DCs is not straight-
forward and it is important to consider the effects on secondary off- 
target populations. 

2. Energy balance 

2.1. Obesity 

Obesity has reached pandemic proportions over the past 50 years. 
According to the World Health Organization, its prevalence nearly 
tripled from 1975 to 2016 and about 13% of people are obese today. 
During the hominids’ evolution, selective pressure has favored the 
adaptation to energy stress caused by frequent nutrient deprivation 
[59]. This may explain why we lack efficient immune mechanisms to 
protect us against current overnutrition and sedentarism. Obesity is 
characterized by an increased body weight due to an imbalance between 
energy intake and energy expenditure [60]. This is mainly caused by an 
excessive food intake associated with unhealthy western diets together 
with sedentary lifestyles. These habits promote a positive energy bal-
ance that favors the accumulation and inflammation of the adipose 

A. Redondo-Urzainqui et al.                                                                                                                                                                                                                  



Immunology Letters 253 (2023) 19–27

22

tissue (AT) and triggers obesity development [61,62]. 
Therefore, diet and physical inactivity are the main drivers of 

obesity. However, genetics, metabolism, microbiota and the circadian 
rhythm also influence its evolution, obscuring its complex etiology [60, 
62]. The most frequent obesity-associated comorbidities are insulin 
resistance, hyperglycemia and hypertension, which in turn increase the 
risk of suffering from severe chronic metabolic and immune diseases 
such as type 2 diabetes, cardiovascular diseases, arthritis, asthma and 
certain cancers [63]. But obesity also leads to a higher risk of death and 
complications from acute diseases, such as viral infections [64,65]. 

2.2. Types and function of adipose tissues 

Recently, the AT has been reconsidered as, not only an energy 
reservoir, but a complex dynamic organ with an important endocrine 
function and a high metabolic activity [66]. Adipocytes produce and 
release adipokines and cytokines that contribute to both metabolic ho-
meostasis and chronic low-grade inflammation under metabolic disor-
der conditions [67]. There are different types of AT: the White Adipose 
Tissue (WAT), the Brown Adipose Tissue (BAT) and beige adipose tissue 
[66]. 

The WAT’s main functions are energy storage, hormone production 
and secretion, and the regulation of local tissue architecture, but also has 
important immune functions (see below) [66,68]. In both, humans and 
mice, WAT is composed by unilocular adipocytes characterized by single 
lipid droplets that are located under the skin (subcutaneous adipose 
tissue or SAT) or in visceral depots adjacent to internal organs (visceral 
adipose tissue or VAT) where energy is stored [69]. SAT stores most of 
the lipids as triglycerides and releases them through lipolysis in the form 
of free fatty acids in periods of high energy demand, for example during 
fasting or physical exercise [70]. When SAT exceeds its storage capacity, 
AT accumulates ectopically in the VAT where it expands through hy-
perplasia (increased adipocyte number) and hypertrophy (increased 
adipocyte size) [71]. 

On the other hand, the BAT is a metabolically active organ that 
contains multilocular adipocytes rich in mitochondria that dissipate 
energy through the uncoupling protein 1 (UCP1) to generate body heat 
(a process known as thermogenesis) [72]. Beige AT has intermediate 
characteristics between both tissues; it morphologically resembles BAT 
but its adipocytes derive from a Myf5− cell lineage, ontogenically 
related to white adipocytes [73]. Beige adipocytes only develop under 
conditions in which UCP1 is expressed, such as exposure to cold or 
stimulation with β3-adrenergic agonists, and reside in WAT depots, 
especially within SAT [71]. 

Although ATs globally orchestrate whole-body energy homeostasis, 
VAT in particular, can be considered the major contributor to obesity- 
associated complications [74]. 

2.3. Immune cell function in the lean adipose tissue: the role of DCs 

In addition to their metabolic and endocrine role, adipocytes host a 
network of innate and adaptive immune cells, making the AT an organ 
that links nutrition, metabolism, and immune functions. While it is well 
known that macrophages play a dominant role in AT homeostasis and 
inflammation [75,76], the contribution of DCs in this tissue is only 
beginning to be uncovered. 

DCs play an anti-inflammatory role in lean AT. The upregulation of 
the WNT/β-catenin pathway in cDC1s promotes IL-10 production, while 
overexpression in cDC2s of the adipogenic peroxisome proliferator- 
activated receptor gamma (PPARγ), a transcription factor that controls 
adipocyte differentiation [77], contains the outbreak of local inflam-
matory responses [78]. cDC2s upregulate PPARγ signaling to limit 

pro-inflammatory signaling cascades [68,78]. However, specific deple-
tion (Zbtb46cre) of either PPARγ or β-catenin in DCs does not impact AT 
homeostasis significantly in mice fed a normal diet. This study did not 
determine the potential role of this depletion in the long term, i.e. during 
aging. In contrast, we and others [79,80] found that the absence of 
cDC1s promotes AT inflammation and obesity in mice fed a chow diet. 
Similarly, we have shown that DC expansion by Flt3L administration 
mitigates DIO and hyperlipidemia in a Batf3-dependent manner [80]. 
Given the prominent role of DCs in orchestrating lymphocyte responses, 
it is conceivable that these cells may in part mediate the role of DC in 
maintaining VAT homeostasis. Lymphocytes are known to exert part of 
their homeostatic functions by preventing classical macrophage acti-
vation. Thus, a healthy VAT harbors regulatory T cells (Tregs), alter-
natively activated macrophages (M2), eosinophils, Th2 lymphocytes, 
type 2 innate lymphoid cells (ILC2s), iNKTs and cDC1s [80,81], that 
control local inflammation and display metabolic roles to maintain VAT 
homeostasis (Fig. 2 central). 

VAT from lean mice harbors a high percentage of Tregs within the 
CD4+ T cell population [82]. Tregs control tissue-specific inflammation 
to prevent tissue damage and favor insulin sensitivity [77,83]. While 
some support that IL-10 produced by Tregs protects against 
obesity-derived insulin resistance [84], others suggest it may be detri-
mental during aging [85]. AT-populating Tregs express PPARγ, being 
crucial for the acquisition of their phenotype and accumulation in VAT 
[86]. 

PPARγ is also expressed in AT macrophages (ATM) and triggers their 
polarization towards an anti-inflammatory phenotype (M2s) [87]. M2s 
predominate over classically activated IFNγ (M1s-like, M1L) macro-
phages in the lean VAT where they exert immunosuppressive properties 
and promote dead adipocyte clearance. These macrophages maintain 
insulin sensitivity by secreting the anti-inflammatory cytokine IL-10 
[75]. ATM from mice and humans show different phenotypes accord-
ing to their local microenvironment. Lipid-associated macrophages ex-
press the lipid sensor TREM2, used to phagocyte and catabolize 
adipocyte-derived lipids. Metabolically-activated macrophages form 
lysosomal synapses with dying adipocytes and internalize free fatty 
acids [68]. It has been also shown that ATM recycle adipocyte-released 
lipid-filled exosomes. The latter are involved in ATM differentiation and 
function, contributing to AT homeostasis [88]. iNKTs abound in a 
healthy VAT (1–20% of resident T-cells) [89]. IFNγ produced by NK1.1+

iNKTs licenses NKs to remove apoptotic macrophages within the AT 
[90], an activity that is partly dependent on cDC1 [80]. Through the 
production of IL-2, IL-4 and IL-10 cytokines, iNKTs also mediate Treg 
proliferation and activation [68]. In addition, adipocytes act as 
non-professional antigen-presenting cells of CD1d/lipid complexes that 
activate anti-inflammatory responses by iNKTs [89,91] (Fig. 2 Central). 

Gamma delta T cells (γδT) have an important role in promoting 
sympathetic innervation. Depleting γδT cells or inhibiting IL-17 receptor 
on brown adipocytes increases obesity and reduces energy expenditure 
[92,93]. However, it is presently unknown which is the role of γδT cells 
in the WAT and whether DC influences the abundance and function of 
these unconventional lymphocytes. 

Eosinophils have been shown to be crucial to maintain AT homeo-
stasis. They produce IL-4 to sustain M2 polarization [94] and contribute 
to adipocyte maturation [95]. ILC2s recruit eosinophils through IL-5 
production and induce macrophage polarization towards an 
anti-inflammatory phenotype through IL-13 production [94,96]. IL-33 
also activates ILC2s and promotes beiging of adipocytes [97] (Fig. 2 
Central). 

In summary, distinct immune populations inhabit the healthy AT 
which are required for its correct function, whereas altered immune 
populations are present in obese AT. 

A. Redondo-Urzainqui et al.                                                                                                                                                                                                                  



Immunology Letters 253 (2023) 19–27

23

3. Excess energy intake 

Excess energy intake is often the leading cause for the development 
of metabolic disease. At an evolutionary level, organisms have evolved 
to deal with short periods of resource unavailability. On the other hand, 
the immune system is an energetically demanding system once acti-
vated. It could be speculated that several cellular and molecular com-
ponents of the immune system have been selected during evolution to 
fine tune the amount of energy left available for the rest of the organism, 
depending on its needs and accessibility to food. A temporary reallo-
cation of energy depots is needed when encountering certain stressors, 
including infection. This process is termed the integrated immunome-
tabolic response. So, from the metabolic point of view, a selective 
pressure during evolution probably favored organisms capable of storing 

more energy. In contrast, nowadays, in most areas of the world, we have 
access to ample energetic resources and our bodies must deal with an 
excess of energy intake which could lead to altered, non-functional, 
immune responses. Now we know that certain high energy intake 
diets induce a low-grade systemic chronic inflammation known as 
metaflammation, and its first inflammatory responses are detected in the 
AT [18,98]. 

3.1. Immune cell function in the adipose tissue during obesity 

Obesity has been associated with an increase of pro-inflammatory 
immune populations in the AT. Whether this pro-inflammatory state is 
the cause or consequence of obesity is still unclear. T lymphocytes and 
monocyte-derived macrophages are one of the first cells to infiltrate the 

Fig. 2. Impact of DC depletion on the immune cells populating the AT during DIO and aging. Center: a healthy AT in WT mice mainly harbors M2 macrophages and 
eosinophils. This type-2 immune milieu depends on ILC2s. Tregs are also abundant, while NKT and NK cells dampen inflammation by eliminating macrophages and 
preventing their pathological expansion. During aging, and in the absence of cDC1 (BATF3− /− mice), a paucity of NKT and NK cells in the AT correlates with the 
accumulation of M1Ls and adipocyte hypertrophy (Bottom Left panel). WT mice fed an HFD show AT inflammation, characterized by the infiltration of IFN-γ 
secreting lymphocytes (Th1, CD8) and Th17 cells (Top left). This HFD-induced AT inflammation is prevented by the absence of DC (FLT3L− /− mice, bottom right). In 
contrast, systemic administration of Flt3L in mice fed an HFD, expands DCs, and reduces AT inflammation in a cDC1 and NK1.1+ cells-dependent fashion (Top right). 

A. Redondo-Urzainqui et al.                                                                                                                                                                                                                  



Immunology Letters 253 (2023) 19–27

24

AT and therefore participate in the onset of inflammation [99]. During 
chronic inflammation, the AT is infiltrated by monocytes expressing 
CCR2. These CCR2+ monocytes differentiate into classically activated 
M1Ls that promote a local immune response [98,100]. IFNγ-producing 
CD8+ T lymphocytes, Th1 cells and monocyte-derived M1Ls activate 
pro-inflammatory responses that affect insulin receptor signaling dis-
rupting glucose homeostasis [98]. B-lymphocytes contribute to VAT 
inflammatory responses by secreting autoreactive IgG antibodies and by 
activating MHC-dependent pro-inflammatory cytokine production by 
both CD4+ and CD8+ T lymphocytes [101]. The formation of crown-like 
structures, where M1Ls surround dead adipocytes, is the major immu-
nohistological hallmark linked to the development of obesity. The role 
of inflammatory macrophages in the response to high-fat diet (HFD) has 
been studied in mouse models that lack CD11c+ cells [102]. DCs are also 
CD11c+, but their role in the inflammatory response to an increased 
energy intake has not been studied in detail. 

4. Dendritic cells in obesity 

The latest studies in humans point towards a positive correlation 
between body mass index and DC in the SAT [103]. Similarly, mice fed 
an HFD show a rapid increase of CD11c+ CD64− leukocytes in the fat 
[104]. Moreover, obesity upregulates the surface expression of MHC, 
CD40, CD80 and CD86 in DCs of AT [59], indicating that these cells 
become activated during obesity and that they play a role in the 
development of the disease (Fig. 2 Top Left). Indeed, Flt3L− /− mice, 
which are devoid of DCs, do not develop obesity on an HFD (Fig. 2 
Bottom Right) [46]. Similarly, CCR7− /− mice, which have less cDCs in 
the AT during DIO, exhibit decreased inflammation, fasting glucose and 
insulin levels [105]. 

However, our group has recently found that an excessive energy 
intake decreases the presence of cDC1s, and not cDC2s, in the VAT of 
male mice. Batf3-deficient mice, lacking cDC1s, spontaneously 
increased body weight and adiposity during aging. This led to impaired 
energy expenditure and glucose tolerance, insulin resistance, dyslipi-
demia, and liver steatosis (fatty liver disease) in middle-aged mice. cDC1 
deficiency caused AT inflammation that was preceded by a paucity of 
NK1.1+ iNKTs and an increased food intake (Fig. 2 Bottom Left). The 
role of iNKT cells in AT homeostasis was previously described by [90, 
106,107]. These results point towards an upstream role of cDC1s. 
However, Batf3− /− mice on an HFD do not become more obese than 
their WT counterparts, probably due to lower cDC1 numbers in wild 
type AT. Others have shown that a Western Diet (WD) curtails β-Catenin 
and PPARγ activation in cDC1s and cDC2s, respectively. This might 
explain why inactivating β-catenin and PPARγ in cDCs does not affect 
weight gain, VAT content, or food intake in mice fed a WD. However, 
these mice displayed elevated serum insulin levels compared to WT mice 
and were significantly less glucose tolerant and more insulin resistant 
than controls [78]. On the other hand, increasing the expression of Flt3L 
systemically, and therefore the number of DCs, reduces the weight gain 
induced by an HFD. This effect is dependent on Batf3 and at least 
partially mediated by NK1.1+ cells (Fig. 2 Top Right) [80]. 

These results imply that cDC1s are necessary to keep the accumu-
lation of AT under control as mice age (Fig. 2 Bottom Left). How these 
cells control fat deposition in AT depots and what the role of other DC 
subsets are in obesity is yet to be determined. One interesting possibility 
is that cDC1s, due to their contribution to an optimal intestinal barrier, 
could promote the expansion of microbiota protective against obesity 
[79]. 

While cDCs may promote the production of IL-10 and modulate tis-
sue metabolism and immune homeostasis [108], pDC accumulation with 
obesity promotes metaflammation. pDCs are recruited to the liver and 
fatty tissues of obese mice and they are associated with the development 
of obesity and insulin resistance. In fact, depletion of pDCs protects mice 
from DIO [109], and increases the amount of Tregs in the VAT [50], 
presumably via a downregulation of the production of IFNα. However, it 

is not only the overall energetic balance that regulates the AT inflam-
matroy status. 

Particular dietary components have been shown to affect the in-
flammatory status of DCs in vitro. MoDCs derived from human PBMCs 
exposed to high fructose produce more IL-6 and IL-1β and induce a 
higher IFN-γ secretion from T cells than those exposed to glucose [110]. 
Pro-inflammatory responses of DCs in a high fructose environment were 
found to be independent of the major known metabolic regulators or 
glycolytic control. Instead, DC activation on acute exposure to fructose 
was via activation of the receptor for advanced glycation end products in 
response to their increased accumulation [110]. 

5. Dendritic cells in hepatic steatosis 

Guilliams et al. [111] show that cDCs in the liver lie mostly close to 
the portal vein, and that both CD103+ and CD103− cDC1s exist in the 
liver. In our study, we noted that Batf3− /− mice fed a chow diet devel-
oped liver steatosis with age, whereas Flt3L treatment decreased hepa-
tomegaly [80]. Moreover, another study showed that adoptive transfer 
of CD103+ cDC1s to Batf3 attenuates the inflammation in established 
murine steatohepatitis [112]. However, a recent study by the Amit 
group found that cDCs increase in the liver of mice that developed 
non-alcoholic steatohepatitis on a methionine and choline-deficient 
diet. This was also the case for animals that were on an HFD or a 
western diet [113]. Here, a methionine- and choline-deficient diet 
induced the proliferation of blood-circulating cDC progenitors in mice. 

More interestingly, the Amit group found that depleting XCR1+ cells 
reduced the development of hepatic steatosis in mice on a choline- 
deficient and high fat diet [113]. This would imply that diets and the 
metabolic status of the organism could have a big impact on the 
development of cDCs, influencing whether their role is protective or 
counterproductive in the development of disease. In human livers, 
several groups have found a negative correlation between the numbers 
of CD141+ cDC1 and the development of both non-alcoholic steatohe-
patitis, non-alcoholic fatty liver disease and hyperglycemia [114,115]. 

6. Dendritic cells during diet interventions and decreased 
energy intake 

6.1. The ketogenic diet 

The ketogenic diet (KD) is a very low carbohydrate-eating plan, with 
a moderate intake of protein, and high in fat. It exposes the organism to a 
carbohydrate starvation-like situation while exposing them to high 
levels of fat. This forces it to obtain energy from the latter almost 
exclusively. Therefore, ketones bodies are produced from acetyl-coA to 
supply energy to the brain [116,117]. The first step required for keto-
genesis is the lipolysis of fatty acids into free fatty acids that are then 
transported from the adipocyte to hepatocyte’s mitochondria, where 
they are oxidized to acetyl-CoA [118]. Under physiological conditions, 
this acetyl-coA is released into the bloodstream and continues its 
oxidation through the Krebs cycle to form energy in the form of ATP. 
Recently, the KD has been used to combat obesity [116,119], although 
neither the metabolic benefits nor the mechanism by which it influences 
weight loss have been deciphered. Recently, the effects of the KD on 
immune cells in the mouse AT have been studied. γδTs are involved in 
suppressing AT inflammation in obese mice fed a KD in the short term (1 
week). In this same article, they describe an increase of both cDC1s and 
cDC2s, but a decrease in migratory DCs in the AT of mice fed a 
short-term KD. However, with a long-term KD (2–3 months) mice 
became obese, associated with an increased macrophage population and 
reduced γδTs in the AT [120]. 

6.2. Fasting and intermittent fasting 

Dietary restriction regimens have beneficial effects on health and 

A. Redondo-Urzainqui et al.                                                                                                                                                                                                                  



Immunology Letters 253 (2023) 19–27

25

longevity. Fasting is a condition where no or minimal food is consumed 
for periods ranging 13 h to 3 weeks. Caloric restriction reduces the daily 
caloric intake 20–40% below the standard but maintains the meal fre-
quency [121]. 

Regarding DC populations, mice fed an energy restricted diet (by 
40%) exhibit increased myeloid progenitors, but decreased common DC 
progenitors, cDCs and pDCs, reducing CD8a+ cDC1 and pDC subsets, but 
not CD11b+ cDCs in spleen [122]. It has been reported that short-term 
fasting enhances the abundance of CD103+ CD11b− DCs within the in-
testinal innate immune cells of mice [123] and decreases circulating 
monocytes and CD141+DCs, equivalent to cDC1s, in humans [124]. Our 
group has reported that fasting mice for 36 h increases the amount of 
cDC1s in the AT of mice [80]. 

Intermittent fasting (IF) is a nutritional strategy that alternates 
fasting periods of 16–48 h and eating periods of 8–120 h [125]. This 
periodic energy restriction of IF improves metabolic homeostasis in mice 
through AT thermogenesis, VEGF-induced alternative activation of 
macrophages (M2s) and increased insulin sensitivity [126]. IF has been 
shown to induce autophagy, a process that constantly renews our cells, 
preventing the accumulation of waste products and apoptotic cells 
[127]. This cell clearance system induced by IF boosts up the immune 
system and therefore, has beneficial effects against diseases including 
SARS-CoV-2 [127]. IF also reduces cytokines such as IL-6 and TNF-α 
modulating inflammatory responses [127]. However, we found no 
research looking at DC populations during IF. Therefore, fasting and 
intermittent fasting show a myriad of health benefits that make them a 
potential therapy strategy against many different diseases. 

6.3. Anorexia 

Primary malnutrition and anorexia nervosa, both chronic anorexic 
conditions, induce depletion of cells in the BM, leukopenia and a 
decreased functionality of DCs [128,129]. Contrary to chronic malnu-
trition, behavioral fasting can be beneficial for the host in response to 
certain pathogens, but not others [130,131]. Systemic production of 
IL-1β is associated with the induction of anorexigenic prostaglandin E2 
at the blood brain barrier, and the suppression of appetite [132]. With 
respect to DCs, production of type I interferon by pDCs has been seen to 
induce somatostatin, and reduce ghrelin production, thereby inhibiting 
appetite in response to viral infections [133]. Therefore, there are signs 
that DCs are likely involved in sepsis-induced behavioral anorexia. 

7. Increased energy expenditure 

The principal determinants of energy expenditure are body size and 
body composition, food intake and physical activity [134]. Exercise is 
the energy expenditure counterpart to increased energy intake, pre-
venting obesity and a hoard of other comorbidities associated with 
aging, fragility and senescence. In humans, skeletal muscle mainly uses 
local glycogen deposits as its fuel during exercise. On the other hand, in 
mice glycogen usage is much more dependent on liver depots. When 
glycogen depots are depleted, glucose uptake from the blood is induced, 
preventing excess glucose obtained from the diet to be transformed into 
fat depots. It is largely seen as an anti-inflammatory activity [135]. 
When done acutely, it promotes an increase in blood circulation of 
leukocytes, followed by a rapid decrease back to baseline, within hours. 
However, long-term exercise reduces the number of pro-inflammatory 
monocytes in circulation, but also has profound effects on other im-
mune populations. The anti-inflammatory effects of exercise have been 
associated with multiple factors. A reduced VAT mass increases the 
production of adiponectin (an anti-inflammatory adipokine), while 
decreasing the production of pro-inflammatory cytokines. It also rapidly 
increases the release of IL-6 by skeletal muscle, followed by a production 
of IL-10 [135]. 

Looking specifically at DC populations, in marathon runners, the 
levels of cDC2s increased only after the race, but returned to baseline 

after 72 h; while pDCs increased during pre-marathon training but 
decreased acutely after the race and had almost returned to baseline 
after 72 h [136]. In human multiple sclerosis patients, acute exercise 
transiently induces the expression of Flt3L in blood, necessary for the 
expansion of DCs. This results in an increased presence of both cDCs and 
pDCs. Both types of cells increased their expression of CD62L and CCR5, 
a sign of migration from the blood into the lymphatic system. All of these 
changes reversed back to baseline 2 h after the end of the exercise [137]. 
In a study in Chinese women, regular exercise did not change the DC 
populations in blood. However, their production of IFNα and IL-12 after 
stimulation was increased, implying that regular exercise increases the 
pro-inflammatory properties of DCs [138]. 

Switching to animals, in a mouse asthma model, one month of ex-
ercise decreased the production of cytokines by BM-derived DCs and the 
production of type 2 cytokines in bronchoalveolar lavage cells [139]. In 
a rat model, the number of DCs and their activity against tumor cells 
were enhanced after a 5-week periodized exercise training with active 
recovery [140]. In another study, rats were trained with a progressively 
increasing load for 9 weeks. Their results revealed that at 36 h and 7 
days post-training, DC count and function were decreased whereas NKTs 
were only reduced at 7 days after training [141,142]. 

Together, these studies point towards an acute activation of DCs 
during and shortly after exercise. In rodents the long-term effects of 
chronic exercise on DC numbers and function seemed to be dependent 
on the model. 

8. Concluding remarks 

DCs comprise a heterogeneous group of innate cells that have a 
unique combination of abilities to process antigens while decoding and 
integrating signals from their environment, which are then transmitted 
to lymphocytes. Through their essential role in priming naïve lympho-
cytes, they are able to lead the adaptive immune response to changes in 
host metabolism. Although DCs have a clear impact on the host meta-
bolic response to overeating - that deserves more attention - their role 
during decreased energy intake through fasting or exercise is still rela-
tively unknown. Moreover, it is still not entirely clear how these adap-
tive mechanisms to metabolic stress work, how DCs orchestrate these 
responses and what cellular and molecular mechanisms underlie them. 
While the interactions between DCs and other cells in tissues and organs 
involved in energy homeostasis are gradually being characterized, the 
outcome of the interaction of DCs with adipocytes, hepatocytes or 
myocytes and how it is influenced by the interaction with other immune 
cells needs to be further explored. Unravelling these interactions will 
require new specific mouse models that overcome the limitations of 
current ones. This will allow us to manipulate these DC-related path-
ways to prevent disease progression. 

Funding 

Work in the S.I. laboratory is funded by the Spanish Ministerio de 
Ciencia, Innovación (MICINN), Agencia Estatal de Investigación (AEI) 
and Fondo Europeo de Desarrollo Regional (FEDER), PID2021- 
125415OB-I00, and RYC-2016-19463. A.R. is a recipient of a research 
assistance scholarship of the Community of Madrid (CT4/21/PEJ-2020- 
AI/BMD-18164). 

Declaration of Competing Interest 

The authors declare that they have no competing interests related to 
this work. 

References 

[1] S.H. Moller, L. Wang, P.C. Ho, Metabolic programming in dendritic cells tailors 
immune responses and homeostasis, Cell Mol. Immunol. 19 (3) (2022) 370–383. 

A. Redondo-Urzainqui et al.                                                                                                                                                                                                                  

http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0001
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0001


Immunology Letters 253 (2023) 19–27

26

[2] S. Zhang, M. Chopin, S.L. Nutt, Type 1 conventional dendritic cells: ontogeny, 
function, and emerging roles in cancer immunotherapy, Trends Immunol. 42 (12) 
(2021) 1113–1127. 

[3] A.D. Garg, P. Agostinis, Cell death and immunity in cancer: from danger signals to 
mimicry of pathogen defense responses, Immunol. Rev. 280 (1) (2017) 126–148. 

[4] T. Ohteki, S. Kawamura, N. Onai, Commitment to dendritic cells and monocytes, 
Int. Immunol. 33 (12) (2021) 815–819. 

[5] C.E. Macdougall, M.P. Longhi, Adipose tissue dendritic cells in steady-state, 
Immunology 156 (3) (2019) 228–234. 

[6] T. Worbs, S.I. Hammerschmidt, R. Forster, Dendritic cell migration in health and 
disease, Nat. Rev. Immunol. 17 (1) (2017) 30–48. 

[7] M. Guilliams, et al., Unsupervised high-dimensional analysis aligns dendritic cells 
across tissues and species, Immunity 45 (3) (2016) 669–684. 

[8] K. Shortman, Y.J. Liu, Mouse and human dendritic cell subtypes, Nat. Rev. 
Immunol. 2 (3) (2002) 151–161. 

[9] J.M. den Haan, M.J. Bevan, Constitutive versus activation-dependent cross- 
presentation of immune complexes by CD8(+) and CD8(-) dendritic cells in vivo, 
J. Exp. Med. 196 (6) (2002) 817–827. 

[10] L. Bonifaz, et al., Efficient targeting of protein antigen to the dendritic cell 
receptor DEC-205 in the steady state leads to antigen presentation on major 
histocompatibility complex class I products and peripheral CD8+ T cell tolerance, 
J. Exp. Med. 196 (12) (2002) 1627–1638. 

[11] D. Dudziak, et al., Differential antigen processing by dendritic cell subsets in vivo, 
Science 315 (5808) (2007) 107–111. 

[12] S. Iborra, et al., Optimal generation of tissue-resident but not circulating memory 
T cells during viral infection requires crosspriming by DNGR-1(+) dendritic cells, 
Immunity 45 (4) (2016) 847–860. 

[13] J.P. Bottcher, et al., NK cells stimulate recruitment of cDC1 into the tumor 
microenvironment promoting cancer immune control, Cell 172 (5) (2018), e14. 

[14] Y.D. Woo, et al., The invariant natural killer T cell-mediated chemokine X-C motif 
chemokine ligand 1-X-C motif chemokine receptor 1 axis promotes allergic 
airway hyperresponsiveness by recruiting CD103(+) dendritic cells, J. Allergy 
Clin. Immunol. 142 (6) (2018), e12. 

[15] M. Enamorado, et al., Enhanced anti-tumour immunity requires the interplay 
between resident and circulating memory CD8(+) T cells, Nat. Commun. 8 (2017) 
16073. 

[16] K. Hildner, et al., Batf3 deficiency reveals a critical role for CD8alpha+ dendritic 
cells in cytotoxic T cell immunity, Science 322 (5904) (2008) 1097–1100. 

[17] B. Wang, et al., Targeting of the non-mutated tumor antigen HER2/neu to mature 
dendritic cells induces an integrated immune response that protects against breast 
cancer in mice, Breast Cancer Res. 14 (2) (2012) R39. 

[18] S. Sundara Rajan, M.P. Longhi, Dendritic cells and adipose tissue, Immunology 
149 (4) (2016) 353–361. 

[19] H. Soares, et al., A subset of dendritic cells induces CD4+ T cells to produce IFN- 
gamma by an IL-12-independent but CD70-dependent mechanism in vivo, J. Exp. 
Med. 204 (5) (2007) 1095–1106. 

[20] M. Guilliams, et al., Dendritic cells, monocytes and macrophages: a unified 
nomenclature based on ontogeny, Nat. Rev. Immunol. 14 (8) (2014) 571–578. 

[21] C.C. Brown, et al., Transcriptional basis of mouse and human dendritic cell 
heterogeneity, Cell 179 (4) (2019), e24. 

[22] A. Musumeci, et al., What makes a pDC: recent advances in understanding 
plasmacytoid DC development and heterogeneity, Front. Immunol. 10 (2019) 
1222. 

[23] Y. Ye, et al., Plasmacytoid dendritic cell biology and its role in immune-mediated 
diseases, Clin. Transl. Immunol. 9 (5) (2020) e1139. 

[24] G. Hoeffel, et al., Antigen crosspresentation by human plasmacytoid dendritic 
cells, Immunity 27 (3) (2007) 481–492. 

[25] P. See, et al., Mapping the human DC lineage through the integration of high- 
dimensional techniques, Science 356 (6342) (2017). 

[26] A.C. Villani, et al., Single-cell RNA-seq reveals new types of human blood 
dendritic cells, monocytes, and progenitors, Science 356 (6335) (2017). 

[27] L. Ziegler-Heitbrock, et al., Reclassifying plasmacytoid dendritic cells as innate 
lymphocytes, Nat. Rev. Immunol. (2022). 

[28] J.Y. Shin, et al., A recently described type 2 conventional dendritic cell (cDC2) 
subset mediates inflammation, Cell. Mol. Immunol. 17 (12) (2020) 1215–1217. 

[29] K.V. Chow, et al., Heterogeneity, functional specialization and differentiation of 
monocyte-derived dendritic cells, Immunol. Cell Biol. 95 (3) (2017) 244–251. 

[30] K.L. Lewis, et al., Notch2 receptor signaling controls functional differentiation of 
dendritic cells in the spleen and intestine, Immunity 35 (5) (2011) 780–791. 

[31] Y. Kumamoto, et al., CD301b(+) dermal dendritic cells drive T helper 2 cell- 
mediated immunity, Immunity 39 (4) (2013) 733–743. 

[32] B. Johansson-Lindbom, et al., Functional specialization of gut CD103+ dendritic 
cells in the regulation of tissue-selective T cell homing, J. Exp. Med. 202 (8) 
(2005) 1063–1073. 

[33] O. Schulz, et al., Intestinal CD103+, but not CX3CR1+, antigen sampling cells 
migrate in lymph and serve classical dendritic cell functions, J. Exp. Med. 206 
(13) (2009) 3101–3114. 

[34] J.L. Coombes, et al., A functionally specialized population of mucosal CD103+
DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid- 
dependent mechanism, J. Exp. Med. 204 (8) (2007) 1757–1764. 

[35] C.M. Sun, et al., Small intestine lamina propria dendritic cells promote de novo 
generation of Foxp3 T reg cells via retinoic acid, J. Exp. Med. 204 (8) (2007) 
1775–1785. 

[36] G. Goverse, et al., Diet-derived short chain fatty acids stimulate intestinal 
epithelial cells to induce mucosal tolerogenic dendritic cells, J. Immunol. 198 (5) 
(2017) 2172–2181. 

[37] D. Sancho, et al., Identification of a dendritic cell receptor that couples sensing of 
necrosis to immunity, Nature 458 (7240) (2009) 899–903. 

[38] S. Iborra, et al., The DC receptor DNGR-1 mediates cross-priming of CTLs during 
vaccinia virus infection in mice, J. Clin. Invest. 122 (5) (2012) 1628–1643. 

[39] M. Merad, et al., The dendritic cell lineage: ontogeny and function of dendritic 
cells and their subsets in the steady state and the inflamed setting, Annu. Rev. 
Immunol. 31 (2013) 563–604. 

[40] M. Cabeza-Cabrerizo, et al., Dendritic cells revisited, Annu. Rev. Immunol. 39 
(2021) 131–166. 

[41] D.A. Anderson 3rd, et al., Genetic models of human and mouse dendritic cell 
development and function, Nat. Rev. Immunol. 21 (2) (2021) 101–115. 

[42] S. Boulet, et al., The orphan nuclear receptor NR4A3 controls the differentiation 
of monocyte-derived dendritic cells following microbial stimulation, Proc. Natl. 
Acad. Sci. U. S. A., 116 (30) (2019) 15150–15159. 

[43] S. Jung, et al., In vivo depletion of CD11c+ dendritic cells abrogates priming of 
CD8+ T cells by exogenous cell-associated antigens, Immunity 17 (2) (2002) 
211–220. 

[44] C. Waskow, et al., The receptor tyrosine kinase Flt3 is required for dendritic cell 
development in peripheral lymphoid tissues, Nat. Immunol. 9 (6) (2008) 
676–683. 

[45] F. Ginhoux, et al., The origin and development of nonlymphoid tissue CD103+
DCs, J. Exp. Med. 206 (13) (2009) 3115–3130. 

[46] F.J. Cueto, D. Sancho, The Flt3L/Flt3 axis in dendritic cell biology and cancer 
immunotherapy, Cancers (Basel) 13 (7) (2021). 

[47] M.M. Meredith, et al., Expression of the zinc finger transcription factor zDC 
(Zbtb46, Btbd4) defines the classical dendritic cell lineage, J. Exp. Med. 209 (6) 
(2012) 1153–1165. 

[48] A.T. Satpathy, et al., Zbtb46 expression distinguishes classical dendritic cells and 
their committed progenitors from other immune lineages, J. Exp. Med. 209 (6) 
(2012) 1135–1152. 

[49] N.E. Papaioannou, et al., Environmental signals rather than layered ontogeny 
imprint the function of type 2 conventional dendritic cells in young and adult 
mice, Nat. Commun. 12 (1) (2021) 464. 

[50] C. Li, et al., Interferon-alpha-producing plasmacytoid dendritic cells drive the loss 
of adipose tissue regulatory T cells during obesity, Cell Metab. 33 (8) (2021), e5. 

[51] M. Swiecki, et al., Plasmacytoid dendritic cell ablation impacts early interferon 
responses and antiviral NK and CD8(+) T cell accrual, Immunity 33 (6) (2010) 
955–966. 

[52] S. Ali, et al., Sources of type I interferons in infectious immunity: plasmacytoid 
dendritic cells not always in the driver’s seat, Front. Immunol. 10 (2019) 778. 

[53] B. Reizis, Plasmacytoid dendritic cells: development, regulation, and function, 
Immunity 50 (1) (2019) 37–50. 

[54] M. Martinez-Lopez, et al., Batf3-dependent CD103+ dendritic cells are major 
producers of IL-12 that drive local Th1 immunity against Leishmania major 
infection in mice, Eur. J. Immunol. 45 (1) (2015) 119–129. 

[55] Z. Qiu, et al., Cutting edge: Batf3 expression by CD8 T cells critically regulates the 
development of memory populations, J. Immunol. 205 (4) (2020) 901–906. 

[56] R. Mattiuz, et al., Novel cre-expressing mouse strains permitting to selectively 
track and edit type 1 conventional dendritic cells facilitate disentangling their 
complexity in vivo, Front. Immunol. 9 (2018) 2805. 

[57] T.T. Liu, et al., Ablation of cDC2 development by triple mutations within the Zeb2 
enhancer, Nature 607 (7917) (2022) 142–148. 

[58] S. Kuhn, J. Yang, F. Ronchese, Monocyte-derived dendritic cells are essential for 
CD8(+) T cell activation and antitumor responses after local immunotherapy, 
Front. Immunol. 6 (2015) 584. 

[59] A.H. Lee, V.D. Dixit, Dietary regulation of immunity, Immunity 53 (3) (2020) 
510–523. 

[60] P. Gonzalez-Muniesa, et al., Obesity, Nat. Rev. Dis. Primers 3 (2017) 17034. 
[61] J.O. Hill, H.R. Wyatt, J.C. Peters, Energy balance and obesity, Circulation 126 (1) 

(2012) 126–132. 
[62] R. San-Cristobal, et al., Contribution of macronutrients to obesity: implications 

for precision nutrition, Nat. Rev. Endocrinol. 16 (6) (2020) 305–320. 
[63] A.S. Greenberg, M.S. Obin, Obesity and the role of adipose tissue in inflammation 

and metabolism, Am. J. Clin. Nutr. 83 (2) (2006) 461S–465S. 
[64] A. Petersen, et al., The role of visceral adiposity in the severity of COVID-19: 

highlights from a unicenter cross-sectional pilot study in Germany, Metabolism 
110 (2020), 154317. 

[65] T. Turk Wensveen, et al., Type 2 diabetes and viral infection; cause and effect of 
disease, Diabetes Res. Clin. Pract. 172 (2021), 108637. 

[66] L. Scheja, J. Heeren, The endocrine function of adipose tissues in health and 
cardiometabolic disease, Nat. Rev. Endocrinol. 15 (9) (2019) 507–524. 

[67] R. Hariharan, et al., The dietary inflammatory index, obesity, type 2 diabetes, and 
cardiovascular risk factors and diseases, Obes. Rev. 23 (1) (2022) e13349. 

[68] W.V. Trim, L. Lynch, Immune and non-immune functions of adipose tissue 
leukocytes, Nat. Rev. Immunol. 22 (6) (2022) 371–386. 

[69] A. Weinstock, et al., Leukocyte heterogeneity in adipose tissue, including in 
obesity, Circ. Res. 126 (11) (2020) 1590–1612. 

[70] A. Chait, L.J. den Hartigh, Adipose tissue distribution, inflammation and its 
metabolic consequences, including diabetes and cardiovascular disease, Front. 
Cardiovasc. Med. 7 (2020) 22. 

[71] P. Morigny, et al., Lipid and glucose metabolism in white adipocytes: pathways, 
dysfunction and therapeutics, Nat. Rev. Endocrinol. 17 (5) (2021) 276–295. 

[72] S. Kajimura, B.M. Spiegelman, P. Seale, Brown and beige fat: physiological roles 
beyond heat generation, Cell Metab. 22 (4) (2015) 546–559. 

[73] A.C. Lehnig, K.I. Stanford, Exercise-induced adaptations to white and brown 
adipose tissue, J. Exp. Biol. 221 (Pt Suppl 1) (2018). 

A. Redondo-Urzainqui et al.                                                                                                                                                                                                                  

http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0002
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0002
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0002
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0003
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0003
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0004
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0004
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0005
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0005
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0006
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0006
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0007
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0007
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0008
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0008
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0009
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0009
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0009
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0010
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0010
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0010
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0010
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0011
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0011
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0012
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0012
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0012
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0013
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0013
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0014
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0014
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0014
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0014
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0015
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0015
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0015
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0016
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0016
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0017
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0017
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0017
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0018
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0018
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0019
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0019
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0019
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0020
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0020
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0021
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0021
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0022
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0022
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0022
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0023
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0023
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0024
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0024
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0025
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0025
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0026
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0026
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0027
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0027
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0028
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0028
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0029
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0029
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0030
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0030
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0031
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0031
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0032
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0032
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0032
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0033
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0033
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0033
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0034
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0034
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0034
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0035
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0035
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0035
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0036
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0036
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0036
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0037
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0037
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0038
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0038
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0039
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0039
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0039
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0040
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0040
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0041
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0041
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0042
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0042
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0042
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0043
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0043
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0043
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0044
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0044
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0044
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0045
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0045
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0046
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0046
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0047
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0047
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0047
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0048
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0048
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0048
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0049
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0049
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0049
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0050
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0050
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0051
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0051
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0051
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0052
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0052
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0053
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0053
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0054
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0054
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0054
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0055
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0055
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0056
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0056
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0056
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0057
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0057
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0058
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0058
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0058
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0059
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0059
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0060
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0061
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0061
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0062
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0062
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0063
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0063
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0064
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0064
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0064
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0065
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0065
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0066
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0066
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0067
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0067
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0068
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0068
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0069
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0069
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0070
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0070
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0070
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0071
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0071
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0072
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0072
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0073
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0073


Immunology Letters 253 (2023) 19–27

27

[74] M. Longo, et al., Adipose tissue dysfunction as determinant of obesity-associated 
metabolic complications, Int. J. Mol. Sci. 20 (9) (2019). 

[75] D. Thomas, C. Apovian, Macrophage functions in lean and obese adipose tissue, 
Metabolism 72 (2017) 120–143. 

[76] B. Lu, et al., Adipose tissue macrophages in aging-associated adipose tissue 
function, J. Physiol. Sci. 71 (1) (2021) 38. 

[77] M. Becker, M.K. Levings, C. Daniel, Adipose-tissue regulatory T cells: critical 
players in adipose-immune crosstalk, Eur. J. Immunol. 47 (11) (2017) 
1867–1874. 

[78] C.E. Macdougall, et al., Visceral adipose tissue immune homeostasis is regulated 
by the crosstalk between adipocytes and dendritic cell subsets, Cell Metab. 27 (3) 
(2018), e4. 

[79] H. Hamade, et al., BATF3 protects against metabolic syndrome and maintains 
intestinal epithelial homeostasis, Front. Immunol. 13 (2022), 841065. 

[80] E. Hernandez-Garcia, et al., Conventional type 1 dendritic cells protect against 
age-related adipose tissue dysfunction and obesity, Cell Mol. Immunol. 19 (2) 
(2022) 260–275. 

[81] A. Castoldi, et al., The macrophage switch in obesity development, Front. 
Immunol. 6 (2015) 637. 

[82] C. Li, R.G. Spallanzani, D. Mathis, Visceral adipose tissue Tregs and the cells that 
nurture them, Immunol. Rev. 295 (1) (2020) 114–125. 

[83] C. Campbell, A. Rudensky, Roles of regulatory T cells in tissue pathophysiology 
and metabolism, Cell Metab. 31 (1) (2020) 18–25. 

[84] A. Kalathookunnel Antony, Z. Lian, H. Wu, T cells in adipose tissue in aging, 
Front. Immunol. 9 (2018) 2945. 

[85] L.Y. Beppu, et al., Tregs facilitate obesity and insulin resistance via a Blimp-1/IL- 
10 axis, JCI Insight 6 (3) (2021). 

[86] D. Cipolletta, et al., PPAR-gamma is a major driver of the accumulation and 
phenotype of adipose tissue Treg cells, Nature 486 (7404) (2012) 549–553. 

[87] M. Hamaguchi, S. Sakaguchi, Regulatory T cells expressing PPAR-gamma control 
inflammation in obesity, Cell Metab. 16 (1) (2012) 4–6. 

[88] S.E. Flaherty 3rd, et al., A lipase-independent pathway of lipid release and 
immune modulation by adipocytes, Science 363 (6430) (2019) 989–993. 

[89] R.J. van Eijkeren, et al., Endogenous lipid antigens for invariant natural killer T 
cells hold the reins in adipose tissue homeostasis, Immunology 153 (2) (2018) 
179–189. 

[90] N.M. LaMarche, et al., Distinct iNKT cell populations use IFNgamma or ER stress- 
induced IL-10 to control adipose tissue homeostasis, Cell Metab. 32 (2) (2020), 
e6. 

[91] J.Y. Huh, et al., Deletion of CD1d in adipocytes aggravates adipose tissue 
inflammation and insulin resistance in obesity, Diabetes 66 (4) (2017) 835–847. 

[92] B. Hu, et al., Gammadelta T cells and adipocyte IL-17RC control fat innervation 
and thermogenesis, Nature 578 (7796) (2020) 610–614. 

[93] A. Sakers, et al., Adipose-tissue plasticity in health and disease, Cell 185 (3) 
(2022) 419–446. 

[94] D.E. Lackey, J.M. Olefsky, Regulation of metabolism by the innate immune 
system, Nat. Rev. Endocrinol. 12 (1) (2016) 15–28. 

[95] E.H. Lee, et al., Eosinophils support adipocyte maturation and promote glucose 
tolerance in obesity, Sci. Rep. 8 (1) (2018) 9894. 

[96] A.B. Molofsky, et al., Innate lymphoid type 2 cells sustain visceral adipose tissue 
eosinophils and alternatively activated macrophages, J. Exp. Med. 210 (3) (2013) 
535–549. 

[97] J.R. Brestoff, et al., Group 2 innate lymphoid cells promote beiging of white 
adipose tissue and limit obesity, Nature 519 (7542) (2015) 242–246. 

[98] A. Christ, M. Lauterbach, E. Latz, Western diet and the immune system: an 
inflammatory connection, Immunity 51 (5) (2019) 794–811. 

[99] S. Kiran, et al., High fat diet-induced CD8(+) T cells in adipose tissue mediate 
macrophages to sustain low-grade chronic inflammation, Front. Immunol. 12 
(2021), 680944. 

[100] P.J. Murray, et al., Macrophage activation and polarization: nomenclature and 
experimental guidelines, Immunity 41 (1) (2014) 14–20. 

[101] D.A. Winer, et al., B cells promote insulin resistance through modulation of T cells 
and production of pathogenic IgG antibodies, Nat. Med. 17 (5) (2011) 610–617. 

[102] D. Patsouris, et al., Ablation of CD11c-positive cells normalizes insulin sensitivity 
in obese insulin resistant animals, Cell Metab. 8 (4) (2008) 301–309. 

[103] A.D. Hildreth, et al., Single-cell sequencing of human white adipose tissue 
identifies new cell states in health and obesity, Nat. Immunol. 22 (5) (2021) 
639–653. 

[104] L.A. Muir, et al., Frontline science: rapid adipose tissue expansion triggers unique 
proliferation and lipid accumulation profiles in adipose tissue macrophages, 
J. Leukoc. Biol. 103 (4) (2018) 615–628. 

[105] K.W. Cho, et al., Adipose tissue dendritic cells are independent contributors to 
obesity-induced inflammation and insulin resistance, J. Immunol. 197 (9) (2016) 
3650–3661. 

[106] L. Lynch, et al., Regulatory iNKT cells lack expression of the transcription factor 
PLZF and control the homeostasis of T(reg) cells and macrophages in adipose 
tissue, Nat. Immunol. 16 (1) (2015) 85–95. 

[107] L. Lynch, et al., Adipose tissue invariant NKT cells protect against diet-induced 
obesity and metabolic disorder through regulatory cytokine production, 
Immunity 37 (3) (2012) 574–587. 

[108] A.R. Ghosh, et al., Adipose recruitment and activation of plasmacytoid dendritic 
cells fuel metaflammation, Diabetes 65 (11) (2016) 3440–3452. 

[109] T.D. Hannibal, et al., Deficiency in plasmacytoid dendritic cells and type I 
interferon signalling prevents diet-induced obesity and insulin resistance in mice, 
Diabetologia 60 (10) (2017) 2033–2041. 

[110] N. Jaiswal, S. Agrawal, A. Agrawal, High fructose-induced metabolic changes 
enhance inflammation in human dendritic cells, Clin. Exp. Immunol. 197 (2) 
(2019) 237–249. 

[111] M. Guilliams, et al., Spatial proteogenomics reveals distinct and evolutionarily 
conserved hepatic macrophage niches, Cell 185 (2) (2022), e38. 

[112] E.C. Heier, et al., Murine CD103(+) dendritic cells protect against steatosis 
progression towards steatohepatitis, J. Hepatol. 66 (6) (2017) 1241–1250. 

[113] A. Deczkowska, et al., XCR1(+) type 1 conventional dendritic cells drive liver 
pathology in non-alcoholic steatohepatitis, Nat. Med. 27 (6) (2021) 1043–1054. 

[114] J.T. Haas, et al., Transcriptional network analysis implicates altered hepatic 
immune function in NASH development and resolution, Nat. Metab. 1 (6) (2019) 
604–614. 

[115] A. Kelly, et al., CD141(+) myeloid dendritic cells are enriched in healthy human 
liver, J. Hepatol. 60 (1) (2014) 135–142. 

[116] A. Paoli, et al., Beyond weight loss: a review of the therapeutic uses of very-low- 
carbohydrate (ketogenic) diets, Eur. J. Clin. Nutr. 67 (8) (2013) 789–796. 

[117] J.C. Newman, E. Verdin, Ketone bodies as signaling metabolites, Trends 
Endocrinol. Metab. 25 (1) (2014) 42–52. 

[118] P. Puchalska, P.A. Crawford, Multi-dimensional roles of ketone bodies in fuel 
metabolism, signaling, and therapeutics, Cell Metab. 25 (2) (2017) 262–284. 

[119] N. Drabińska, W. Wiczkowski, M.K. Piskuła, Recent advances in the application of 
a ketogenic diet for obesity management, Trends Food Sci. Technol. 110 (2021) 
28–38. 

[120] E.L. Goldberg, et al., Ketogenesis activates metabolically protective gammadelta T 
cells in visceral adipose tissue, Nat. Metab. 2 (1) (2020) 50–61. 

[121] V.D. Longo, M.P. Mattson, Fasting: molecular mechanisms and clinical 
applications, Cell Metab. 19 (2) (2014) 181–192. 

[122] D.M. Duriancik, E.M. Gardner, Energy restriction impairs dendritic cell development 
in C57BL/6 J mice, Mech Ageing Dev. 154 (2016) 9–19. 

[123] Ju, Y.-.J., et al., Short-term fasting enhances the protection against listeria 
monocytogenes infection through changes of intestinal CD103+ dendritic cells. 2020. 

[124] S. Jordan, et al., Dietary intake regulates the circulating inflammatory monocyte 
pool, Cell 178 (5) (2019), e17. 

[125] V.D. Longo, et al., Intermittent and periodic fasting, longevity and disease, Nat. 
Aging 1 (1) (2021) 47–59. 

[126] K.H. Kim, et al., Intermittent fasting promotes adipose thermogenesis and 
metabolic homeostasis via VEGF-mediated alternative activation of macrophage, 
Cell Res. 27 (11) (2017) 1309–1326. 

[127] M.A. Hannan, et al., Intermittent fasting, a possible priming tool for host defense 
against SARS-CoV-2 infection: crosstalk among calorie restriction, autophagy and 
immune response, Immunol. Lett. 226 (2020) 38–45. 

[128] D. Gibson, P.S. Mehler, Anorexia nervosa and the immune system-a narrative 
review, J. Clin. Med. 8 (11) (2019). 

[129] T. Niiya, et al., Impaired dendritic cell function resulting from chronic 
undernutrition disrupts the antigen-specific immune response in mice, J. Nutr. 
137 (3) (2007) 671–675. 

[130] A. Wang, et al., Opposing effects of fasting metabolism on tissue tolerance in 
bacterial and viral inflammation, Cell 166 (6) (2016), e12. 

[131] S. Rao, et al., Pathogen-mediated inhibition of anorexia promotes host survival 
and transmission, Cell 168 (3) (2017), e12. 

[132] M. Bottcher, et al., NF-kappaB signaling in tanycytes mediates inflammation- 
induced anorexia, Mol. Metab. 39 (2020), 101022. 

[133] S. Stutte, et al., Type I interferon mediated induction of somatostatin leads to 
suppression of ghrelin and appetite thereby promoting viral immunity in mice, 
Brain Behav. Immun. 95 (2021) 429–443. 

[134] K.R. Westerterp, Control of energy expenditure in humans, Eur. J. Clin. Nutr. 71 
(3) (2017) 340–344. 

[135] M. Gleeson, et al., The anti-inflammatory effects of exercise: mechanisms and 
implications for the prevention and treatment of disease, Nat. Rev. Immunol. 11 
(9) (2011) 607–615. 

[136] K. Lackermair, et al., Influence of polyphenol-rich diet on exercise-induced 
immunomodulation in male endurance athletes, Appl. Physiol. Nutr. Metab. 42 
(10) (2017) 1023–1030. 

[137] N. Deckx, et al., 12 weeks of combined endurance and resistance training reduces 
innate markers of inflammation in a randomized controlled clinical trial in 
patients with multiple sclerosis, Mediators Inflamm. 2016 (2016), 6789276. 

[138] Q. Zheng, et al., Regular exercise enhances the immune response against 
microbial antigens through up-regulation of toll-like receptor signaling pathways, 
Cell Physiol. Biochem. 37 (2) (2015) 735–746. 

[139] B. Mackenzie, et al., Dendritic cells are involved in the effects of exercise in a 
model of asthma, Med. Sci. Sports Exerc. 48 (8) (2016) 1459–1467. 

[140] H.F. Liao, et al., Effect of a periodized exercise training and active recovery 
program on antitumor activity and development of dendritic cells, J. Sports Med. 
Phys. Fitness 46 (2) (2006) 307–314. 

[141] W. Ru, C. Peijie, Modulation of dendritic cells and NKT cells by excessive exercise 
in rats, J. Med. Biol. Eng. 29 (4) (2009) 190–194. 

[142] W. Ru, C. Peijie, Modulation of NKT cells and Th1/Th2 imbalance after alpha- 
GalCer treatment in progressive load-trained rats, Int. J. Biol. Sci. 5 (4) (2009) 
338–343. 

A. Redondo-Urzainqui et al.                                                                                                                                                                                                                  

http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0074
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0074
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0075
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0075
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0076
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0076
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0077
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0077
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0077
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0078
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0078
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0078
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0079
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0079
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0080
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0080
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0080
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0081
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0081
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0082
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0082
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0083
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0083
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0084
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0084
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0085
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0085
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0086
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0086
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0087
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0087
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0088
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0088
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0089
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0089
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0089
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0090
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0090
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0090
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0091
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0091
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0092
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0092
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0093
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0093
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0094
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0094
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0095
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0095
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0096
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0096
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0096
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0097
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0097
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0098
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0098
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0099
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0099
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0099
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0100
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0100
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0101
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0101
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0102
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0102
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0103
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0103
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0103
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0104
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0104
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0104
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0105
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0105
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0105
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0106
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0106
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0106
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0107
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0107
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0107
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0108
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0108
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0109
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0109
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0109
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0110
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0110
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0110
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0111
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0111
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0112
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0112
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0113
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0113
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0114
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0114
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0114
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0115
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0115
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0116
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0116
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0117
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0117
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0118
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0118
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0119
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0119
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0119
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0120
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0120
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0121
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0121
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0122
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0122
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0124
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0124
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0125
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0125
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0126
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0126
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0126
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0127
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0127
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0127
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0128
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0128
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0129
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0129
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0129
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0130
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0130
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0131
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0131
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0132
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0132
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0133
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0133
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0133
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0134
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0134
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0135
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0135
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0135
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0136
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0136
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0136
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0137
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0137
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0137
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0138
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0138
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0138
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0139
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0139
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0140
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0140
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0140
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0141
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0141
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0142
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0142
http://refhub.elsevier.com/S0165-2478(22)00164-X/sbref0142

	Dendritic cells in energy balance regulation
	1 Introduction to DCs
	1.1 Ontogeny, classification and function in host defense
	1.2 Markers and lineage-specification transcription factors
	1.3 Mouse models for analysis of specific DC functions and for their depletion

	2 Energy balance
	2.1 Obesity
	2.2 Types and function of adipose tissues
	2.3 Immune cell function in the lean adipose tissue: the role of DCs

	3 Excess energy intake
	3.1 Immune cell function in the adipose tissue during obesity

	4 Dendritic cells in obesity
	5 Dendritic cells in hepatic steatosis
	6 Dendritic cells during diet interventions and decreased energy intake
	6.1 The ketogenic diet
	6.2 Fasting and intermittent fasting
	6.3 Anorexia

	7 Increased energy expenditure
	8 Concluding remarks
	Funding
	Declaration of Competing Interest
	References