Mast cells regulate CD4+ T-cell differentiation in the absence of antigen presentation - 06/12/18
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Nicotinamide adenine dinucleotide, mast cells, T cells, antigen presentation, MHC, T-cell receptor, CD4+ T-cell differentiation, dendritic cells, macrophages, Listeria monocytogenes, cytokine
Abbreviations used : APC, BMMC, DAMP, DC, EAE, LPA, MC, NAD+, PAMP, PRR, Rag2, TCR, WASP, WT
Plan
Supported by National Institutes of Health grants R01NS073635 and R01MH110438 (to A.V.), R01 HL096795 and U01 HL126497 (to I.G.), and R01AG039449 (to S.G.T.). H.R.C.B. was supported by the Swiss Society of Cardiac Surgery. M.A.d.l.F was supported by FIS-ISCIII (grant PI10/02 511) and Fundación Ramón Areces (CIVP16A1843). |
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Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 6
P. 1894 - décembre 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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