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Título
Mast cells regulate CD4+ T-cell differentiation in the absence of antigen presentation
Autor
Año del Documento
2018
Editorial
Elsevier
Descripción
Producción Científica
Documento Fuente
Journal of Allergy and Clinical Immunology, 2018, vol. 142, n. 6. p. 1894-1908
Resumen
Background: Given their unique capacity for antigen uptake, processing, and presentation, antigen-presenting cells (APCs) are critical for initiating and regulating innate and adaptive immune responses. We have previously shown the role of nicotinamide adenine dinucleotide (NAD+) in T-cell differentiation independently of the cytokine milieu, whereas the precise mechanisms remained unknown. Objective: The objective of this study is to further dissect the mechanism of actions of NAD+ and determine the effect of APCs on NAD+-mediated T-cell activation. Methods: Isolated dendritic cells and bone marrow–derived mast cells (MCs) were used to characterize the mechanisms of action of NAD+ on CD4+ T-cell fate in vitro. Furthermore, NAD+-mediated CD4+ T-cell differentiation was investigated in vivo by using wild-type C57BL/6, MC−/−, MHC class II−/−, Wiskott-Aldrich syndrome protein (WASP)−/−, 5C.C7 recombination-activating gene 2 (Rag2)−/−, and CD11b-DTR transgenic mice. Finally, we tested the physiologic effect of NAD+ on the systemic immune response in the context of Listeria monocytogenes infection. Results: Our in vivo and in vitro findings indicate that after NAD+ administration, MCs exclusively promote CD4+ T-cell differentiation, both in the absence of antigen and independently of major APCs. Moreover, we found that MCs mediated CD4+ T-cell differentiation independently of MHC II and T-cell receptor signaling machinery. More importantly, although treatment with NAD+ resulted in decreased MHC II expression on CD11c+ cells, MC-mediated CD4+ T-cell differentiation rendered mice resistant to administration of lethal doses of L monocytogenes. Conclusions: Collectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity through MCs exclusively and underscores the therapeutic potential of NAD+ in the context of primary immunodeficiencies and antimicrobial resistance.
Palabras Clave
Mast cells
Mastocitos
T cells
Células T
Antigen presentation
Presentación de antígeno
ISSN
0091-6749
Revisión por pares
SI
Patrocinador
National Institutes of Health (grants R01NS073635 , R01MH110438 , R01HL096795 , U01HL126497 and R01AG039449)
Instituto de Salud Carlos III (grant PI10/02 511)
Fundación Ramón Areces (grant CIVP16A1843)
Instituto de Salud Carlos III (grant PI10/02 511)
Fundación Ramón Areces (grant CIVP16A1843)
Version del Editor
Propietario de los Derechos
© 2018 Elsevier
Idioma
eng
Tipo de versión
info:eu-repo/semantics/publishedVersion
Derechos
openAccess
Aparece en las colecciones
Ficheros en el ítem
La licencia del ítem se describe como Attribution-NonCommercial-NoDerivatives 4.0 Internacional