Person: Muñoz Ruiz, Miguel
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First Name
Miguel
Last Name
Muñoz Ruiz
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Inmunología, Oftalmología y ORL
Area
Identifiers
10 results
Search Results
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Item 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, BrunoThe 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.Item 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 RamónImmunodeficiencies 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.Item 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 deItem 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 RamónItem 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 RamónBackground: 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.Item 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 RamónThe 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.Item 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 RamónHuman 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.Item 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 RamónLas 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.Item Papel del TCR en el desarrollo y función de los linfocitos Tϒδ efectores(2017) Muñoz Ruiz, Miguel; Regueiro, José R.; Fernández Malavé, Edgar; Silva-Santos, BrunoLas células Tγδ se han revelado en los últimos tiempos como un tipo celular básico dentro del sistema inmunológico innato y adaptativo por su capacidad para producir citoquinas a diferentes tiempos y a la posibilidad de actuar contra distintos agentes infecciosos como virus, bacterias, parásitos o incluso contra células tumorales. Las distintas subpoblaciones de linfocitos Tγδ con capacidad de producir IFN-γ o IL-17 principalmente, se generan en el timo de ratón, pero los estados de maduración o señales que dirigen y controlan este proceso de diferenciación no se conocen con exactitud. En este contexto, el TCR parece ser clave para entender el desarrollo de estos linfocitos Tγδ. Se acepta, gracias a diferentes estudios, que las células que reciben una intensidad de señal fuerte a través del TCR son aquellas que tendrán capacidad para producir IFN-γ, mientras que las células que producen IL-17 emergerán por “defecto” durante el desarrollo tímico recibiendo únicamente una señal débil a través del TCR. Sin embargo, este modelo ha sido discutido en los últimos dos años, pues se ha descrito que las células Tγδ del ratón SKG (ratón con una mutación hipomórfica en ZAP-70 que reduce en torno al 90% la capacidad de señalización vía TCR)mantienen intacta su capacidad para producir IFN-γ. No obstante, sí ven afectada la producción de IL-17 (tanto en timo como en periferia). Además otros artículos relacionaron el cambioconformacional del TCR tras activación con el desarrollo de algunas células Tγδ productoras de IL-17. En este punto, nos planteamos abordar esta cuestión desde una perspectiva diferente:disminuir la cantidad de TCRγδ en la superficie celular con el fin de interferir su señalización invivo. Para ello, se generaron y analizaron ratones portadores de mutaciones que afectaban la expresión de CD3γ, CD3δ y CD3ɛ, sin observarse diferencias significativas comparando con ratones control. Sin embargo, cuando se analizó un ratón con haploinsuficiencia simultanea para Cd3g y Cd3d (CD3DH, por Haploinsuficiencia Doble de Cd3), se pudo comprobar cómo efectivamente la expresión del TCRγδ en superficie se encontraba disminuida, pero no la del TCRαβ. Por lo tanto, se consideró que este ratón (la menor expresión del TCRγδ en superficie también implica una menor capacidad de señalización) podría ser una herramienta útil para entender el papel que juega la intensidad de la señal del TCR en el desarrollo de las distintas subpoblaciones efectoras de células Tγδ en el timo. Cabe destacar que este modelo de ratón permite abordar esta pregunta sobre el repertorio total de linfocitos Tγδ (policlonal) y no desde un abordaje monoclonal (ratones transgénicos que expresan un único TCR), como se había descrito en la mayoría de los trabajos relacionados con el tema...Item 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 RamónWe 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.