Mast cells regulate CD4+ T cell differentiation in absence of antigen presentation

Publication date: Available online 20 February 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Hector Rodriguez Cetina Biefer, Timm Heinbokel, Hirofumi Uehara, Virginia Camacho, Koichiro Minami, Yeqi Nian, Suresh Koduru, Rachid El Fatimy, Ionita Ghiran, Alexander J. Trachtenberg, Miguel A. de la Fuente, Haruhito Azuma, Omid Akbari, Stefan G. Tullius, Anju Vasudevan, Abdallah Elkhal
BackgroundGiven 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, while the precise mechanisms remained unknown.ObjectiveThe objective of this study is to further dissect the mechanism of actions of NAD⁺, and to determine the impact of APCs on NAD⁺-mediated T cell activation.MethodsIsolated dendritic cells and bone marrow-derived mast cells 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 using WT C57BL/6, Mast cell^-/-, MHC class ll^-/-, WASP^-/-, 5C.C7 Rag2^-/- and CD11b-DTR transgenic mice. Finally, we tested the physiological impact of NAD⁺ on the systemic immune response in the context of Listeria monocytogenes infection.ResultsOur in vivo and in vitro findings indicate that following NAD⁺ administration MCs, exclusively, promote CD4⁺ T cell differentiation, both in absence of antigen and independently of major APCs. Moreover, we found that MCs mediated CD4⁺ T cell differentiation independently of MHC-II and TCR signaling machinery. More importantly, although treatment with NAD⁺ resulted in a decreased MHC-II expression on CD11c⁺ cells, MC-mediated CD4⁺ T cell differentiation rendered mice resistant to the administration of lethal doses of Listeria monocytogenes.ConclusionsCollectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity via MCs, exclusively, and underscores the therapeutic potential of NAD⁺ in the context of primary immunodeficiencies and antimicrobial resistance.



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