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

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.
(Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)