Person:
Regueiro González-Barros, José Ramón

First Name

José Ramón

Last Name

Regueiro González-Barros

URI

https://hdl.handle.net/20.500.14352/79598

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Medicina

Department

Inmunología, Oftalmología y ORL

Area

Inmunología

Identifiers

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Now showing 1 - 10 of 10

TCR signal strength controls thymic differentiation of discrete proinflammatory gamma-delta T cell subsets
(Nature immunology, 2016) Muñoz Ruiz, Miguel; Ribot, Julie C; Grosso, Ana R; Gonçalves Sousa, Natacha; Pamplona, Ana; Pennington, Daniel J; Regueiro González-Barros, José Ramón; Fernández Malavé, Edgar; Silva Santos, Bruno
The mouse thymus produces discrete gd T cell subsets that make either interferon-g (IFN-g) or interleukin 17 (IL-17), but the role of the T cell antigen receptor (TCR) in this developmental process remains controversial. Here we show that Cd3g+/− Cd3d+/− (CD3 double-haploinsufficient (CD3DH)) mice have reduced TCR expression and signaling strength on gd T cells. CD3DH mice had normal numbers and phenotypes of ab thymocyte subsets, but impaired differentiation of fetal Vg6+ (but not Vg4+) IL-17- producing gd T cells and a marked depletion of IFN-g-producing CD122+ NK1.1+ gd T cells throughout ontogeny. Adult CD3DH mice showed reduced peripheral IFN-g+ gd T cells and were resistant to experimental cerebral malaria. Thus, TCR signal strength within specific thymic developmental windows is a major determinant of the generation of proinflammatory gd T cell subsets and their impact on pathophysiology.
Human congenital T-cell receptor disorders
(LymphoSign Journal, 2015) Marín Marín, Ana Victoria; Garcillán Goyoaga, Beatriz de; Jiménez Reinoso, Anaïs; Muñoz Ruiz, Miguel; Briones Contreras, Alejandro; Fernández Malavé, Edgar; Recio Hoyas, María José; Regueiro González-Barros, José Ramón
Immunodeficiencies of most T-cell receptor (TCR) components (TCRID) have been reported in almost 40 patients worldwide who have also, at times, shown signs of autoimmunity. We updated their clinical, immunological, and molecular features with an emphasis on practical diagnosis, as the range of the disorder grows in complexity with new partial defects. Cellular and animal models are also reviewed and in some cases reveal their limitations for predicting TCRID immunopathology.
Primary T-cell immunodeficiency with functional revertant somatic mosaicism in CD247
(The Journal of Allergy and Clinical Inmunology, 2017) Marín Marín, Ana Victoria; Jiménez Reinoso, Anaïs; Briones Contreras, Alejandro; Muñoz Ruiz, Miguel; Aydogmus, Cigdem; Pasick, Luke J; Couso, Jorge; Mazariegos, Marina S; Álvarez Prado, Ángel F; Blázquez Moreno, Alfonso; Cipe, Funda E; Haskologlu, Sule; Dogu, Figen; Morín, Matías; Moreno Pelayo, Miguel A; García Sánchez, Félix; Gil Herrera, Juana; Fernández Malavé, Edgar; Reyburn, Hugh T; Ramiro, Almudena R; Ikinciogullari,, Aydan; Recio Hoyas, María José; Regueiro González-Barros, José Ramón; Garcillán Goyoaga, Beatriz de
Enrichment of the rare CD41 gd T-cell subset in patients with atypical CD3d deficiency
(Journal of Allergy and Clinical Immunology, 2014) Garcillán Goyoaga, Beatriz de; Mazariegos, Marina S; Fisch, Paul; Resh, Peter C.; Muñoz Ruiz, Miguel; Gil Herrera, Juana; López Granados, Eduardo; Fernández Malavé, Edgar; Regueiro González-Barros, José Ramón
Human CD3γ, but not CD3δ, haploinsufficiency differentially impairs γδ versus αβ surface TCR expression
(BMC Immunology, 2013) Muñoz Ruiz, Miguel; Pérez Flores, Verónica; Garcillán Goyoaga, Beatriz de; Guardo, Alberto C; Mazariegos, Marina S; Takada, Hidetoshi; Allende Martínez, Luis Miguel; Kilic, Sara S; Sanal, Ozden; Roifman, Chaim M; López Granados, Eduardo; Recio Hoyas, María José; Martínez Naves, Eduardo; Fernández Malavé, Edgar; Regueiro González-Barros, José Ramón
Background: The T cell antigen receptors (TCR) of αβ and γδ T lymphocytes are believed to assemble in a similar fashion in humans. Firstly, αβ or γδ TCR chains incorporatea CD3δε dimer, then a CD3γε dimer and finally a ζζ homodimer, resulting in TCR complexes with the same CD3 dimer stoichiometry. Partial reduction in the expression of the highly homologous CD3γ and CD3δ proteins would thus be expected to have a similar impact in the assembly and surface expression of both TCR isotypes. To test this hypothesis, we compared the surface TCR expression of primary αβ and γδ T cells from healthy donors carrying a single null or leaky mutation in CD3G (γ+/−) or CD3D (δ+/−, δ+/leaky) with that of normal controls. Results: Although the partial reduction in the intracellular availability of CD3γ or CD3δ proteins was comparable as a consequence of the mutations, surface TCR expression measured with anti-CD3ε antibodies was significantly more decreased in γδ than in αβ T lymphocytes in CD3γ+/− individuals, whereas CD3δ+/− and CD3δ+/leaky donors showed a similar decrease of surface TCR in both T cell lineages. Therefore, surface γδ TCR expression was more dependent on available CD3γ than surface αβ TCR expression. Conclusions: The results support the existence of differential structural constraints in the two human TCR isotypes regarding the incorporation of CD3γε and CD3δε dimers, as revealed by their discordant surface expression behaviour when confronted with reduced amounts of CD3γ, but not of the homologous CD3δ chain. A modified version of the prevailing TCR assembly model is proposed to accommodate these new data.
CD3G or CD3D Knockdown in Mature, but Not Immature, T Lymphocytes Similarly Cripples the Human TCRαβ Complex
(Frontiers in Cell and Developmental Biology, 2021) Garcillán Goyoaga, Beatriz de; Fuentes, Patricia; Marín Marín, Ana Victoria; Fernández Megido, Rebeca; Chacón Arguedas, Carlos Daniel; S. Mazariegos, Marina; González Laborda, Raquel; Jiménez Reinoso, Anaïs; Muñoz Ruiz, Miguel; Cárdenas Mastracusa, Paula; Fernández-Malavé, Edgar; Toribio, Maria Luisa; Regueiro González-Barros, José Ramón
The human αβ T-cell receptor (TCR) is composed of a variable heterodimer (TCRαβ) and three invariant dimers (CD3γε, CD3δε, and ζζ/CD2472). The role of each invariant chain in the stepwise interactions among TCR chains along the assembly is still not fully understood. Despite the high sequence homology between CD3γ and CD3δ, the clinical consequences of the corresponding immunodeficiencies (ID) in humans are very different (mild and severe, respectively), and mouse models do not recapitulate findings in human ID. To try to understand such disparities, we stably knocked down (KD) CD3D or CD3G expression in the human Jurkat T-cell line and analyzed comparatively their impact on TCRαβ assembly, transport, and surface expression. The results indicated that TCR ensembles were less stable and CD3ε levels were lower when CD3γ, rather than CD3δ, was scarce. However, both defective TCR ensembles were strongly retained in the ER, lacked ζζ/CD2472, and barely reached the T-cell surface (<11% of normal controls) in any of the CD3 KD cells. This is in sharp contrast to human CD3γ ID, whose mature T cells express higher levels of surface TCR (>30% vs. normal controls). CD3 KD of human T-cell progenitors followed by mouse fetal thymus organ cultures showed high plasticity in emerging immature polyclonal T lymphocytes that allowed for the expression of significant TCR levels which may then signal for survival in CD3γ, but not in CD3δ deficiency, and explain the immunological and clinical disparities of such ID cases.
gd T lymphocytes in the diagnosis of human T cell receptor immunodeficiencies
(Frontiers in immunology, 2015) Garcillán Goyoaga, Beatriz de; Marín Marín, Ana Victoria; Jiménez Reinoso, Anaïs; Briones Contreras, Alejandro; Muñoz Ruiz, Miguel; García León, María J; Gil Calle, Juana Nelly; Allende Martínez, Luis Miguel; Martínez Naves, Eduardo; Toribio, Maria Luisa; Regueiro González-Barros, José Ramón
Human T cell receptor (TCR) immunodeficiencies (TCRID) are rare autosomal recessive disorders caused by mutations affecting TCR, CD3, or CD247 chains, which share developmental, functional, and TCR expression defects (1). Their rapid diagnosis is fundamental for patient survival and early hematopoietic stemcell transplantation.Here,we propose that studying gd T cells, which are often neglected, can be helpful for a timely diagnosis. We thus offer a diagnostic flowchart and some lab tricks based on published cases.
Inmunodeficiencias congénitas del receptor de antígeno de los linfocitos T
(Inmunología, 2013) Mazariegos, Marina S; Muñoz Ruiz, Miguel; Reiné Gutiérrez, Jesús; Garcillán Goyoaga, Beatriz de; Recio Hoyas, María José; Fernández Malavé, Edgar; Regueiro González-Barros, José Ramón
Las inmunodeficiencias humanas del TCR son enfermedades autosómicas recesivas con baja prevalencia, caracterizadas por un defecto de expresión del TCR asociado a una linfopenia T selectiva (más leve en el caso de CD3γ, TCRα o CD247, o grave en el caso de CD3δ o CD3??). La ausencia congénita de componentes del TCR tiene un impacto diferencial en el desarrollo y función de los linfocitos T, que depende de la cadena del TCR afectada y de la especie, siendo en algunos casos diferente en los pacientes humanos en comparación con los modelos en ratones. El estudio del inmunofenotipo mediante citometría de flujo, junto con los estudios moleculares, proporciona información esencial para el diagnóstico y el tratamiento, que continúa siendo a día de hoy el trasplante de progenitores hematopoyéticos en los casos asociados a inmunodeficiencia grave.
Lymphocyte integration of complement cues
(Seminars in Cell & Developmental Biology, 2018) Marín Marín, Ana Victoria; Cárdenas, Paula P; Jiménez Reinoso, Anaïs; Muñoz Ruiz, Miguel; Regueiro González-Barros, José Ramón
We address current data, views and puzzles on the emerging topic of regulation of lymphocytes by complement proteins or fragments. Such regulation is believed to take place through complement receptors (CR) and membrane complement regulators (CReg) involved in cell function or protection, respectively, including intracellular signalling. Original observations in B cells clearly support that complement cues through CR improve their performance. Other lymphocytes likely integrate complement-derived signals, as most lymphoid cells constitutively express or regulate CR and CReg upon activation. CR-induced signals, particularly by anaphylatoxins, clearly regulate lymphoid cell function. In contrast, data obtained by CReg crosslinking using antibodies are not always confirmed in human congenital deficiencies or knock-out mice, casting doubts on their physiological relevance. Unsurprisingly, human and mouse complement systems are not completely homologous, adding further complexity to our still fragmentary understanding of complement-lymphocyte interactions.
Project number: PIMCD86/23-24
Simulación virtual de diagnóstico de inmunodeficiencias congénitas para el asentamiento de conocimientos básicos sobre inmunología
(0024) Marín Marín, Ana Victoria; Martínez Naves, Eduardo; Regueiro González-Barros, José Ramón; Tortajada Alonso, Agustín; Cubero Palero, Francisco Javier; Allende Martínez, Luis Miguel; González Granado, Luis Ignacio; Muñoz Ruiz, Miguel; Chacón Arguedas, Carlos Daniel; Fernández Megino, Rebeca; Herrero Alonso, Marta; Estévez Benito, Iván; Fernández Boraita, Julia Belén; Franco Jarava, Clara
La inmunología es una materia transversal que trata conocimientos de biología celular, bioquímica molecular, genética y patología clínica. La docencia que reciben los alumnos de primero de Medicina en nuestra Universidad, cuyas aulas se componen de 80 alumnos aproximadamente, consta de unas 36 horas anuales en una asignatura obligatoria e impartida en el segundo periodo del curso. Dada la gran complejidad inherente en el estudio inmunología, es realmente difícil lograr el interés del grupo por la asignatura a través de las técnicas docentes clásicas. En este proyecto de innovación docente, proponemos una actividad interactiva, parcialmente virtual y con una perspectiva basico-clínica interactiva mediante la cual los alumnos participarán activamente en el diagnóstico de un total de 3 pacientes pediátricos con errores congénitos de la inmunidad durante una única sesión al final del curso. Para ello, dispondremos de 3 casos clínicos reales que describirán enfermedades frecuentes dentro de la especialidad siendo presentados concisamente con datos clínicos a través de la pantalla de la misma aula docente, y de manera simultánea lanzaremos preguntas a través de una plataforma web que permitirá que los alumnos respondan utilizando un “apodo” e individualmente empleando sus teléfonos móviles. Con cada pregunta los alumnos aprenderán a identificar conceptos claves para el diagnóstico de inmunodeficiencias que no pueden abordarse en las clases magistrales por escasez de tiempo, y a la vez autoevaluarán los conocimientos adquiridos hasta el momento.