Mast cells regulate CD4+ T-cell differentiation in the absence of antigen presentation
2018
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.
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