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oai:uvadoc.uva.es:10324/446082021-06-24T07:17:48Zcom_10324_43677com_10324_954com_10324_894col_10324_43678

Mast cells regulate CD4+ T-cell differentiation in the absence of antigen presentation Rodriguez-Cetina Biefer, Héctor Heinbokel, Timm Uehara, Hirofumi Camacho, Virginia Minami, Koichiro Nian, Yeqi Koduru, Suresh El Fatimy, Rachid Ghiran, Ionita Trachtenberg, Alexander J. Fuente García, Miguel Ángel de la Azuma, Haruhito Akbari, Omid Tullius, Stefan G. Vasudevan, Anju Elkhal, Abdallah 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. 2020-12-28T13:49:55Z 2020-12-28T13:49:55Z 2020-12-28T13:49:55Z 2018 info:eu-repo/semantics/article Journal of Allergy and Clinical Immunology, 2018, vol. 142, n. 6. p. 1894-1908 0091-6749 http://uvadoc.uva.es/handle/10324/44608 10.1016/j.jaci.2018.01.038 eng https://www.sciencedirect.com/science/article/pii/S0091674918302811 info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/4.0/ © 2018 Elsevier Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier