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.

中文翻译：

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在没有抗原呈递的情况下肥大细胞调节CD4 ⁺ T细胞分化

背景

鉴于其独特的抗原摄取，加工和呈递能力，抗原呈递细胞（APC）对于启动和调节先天性和适应性免疫应答至关重要。我们先前已经显示了烟酰胺腺嘌呤二核苷酸（NAD ⁺）在T细胞分化中的作用，而与细胞因子环境无关，而确切的机制仍然未知。

客观的

这项研究的目的是进一步剖析NAD ⁺的作用机制，并确定APC对NAD ⁺介导的T细胞活化的影响。

方法

分离的树突状细胞和骨髓肥大细胞（MCs）用于表征NAD ⁺在体外对CD4 ⁺ T细胞命运的作用机制。此外，使用野生型C57BL / 6，MC ^-/-，MHC II类^-/-，Wiskott-Aldrich综合征蛋白（WASP）^-/-，5C对NAD ⁺介导的CD4 ⁺ T细胞分化进行了体内研究.C7重组激活基因2（Rag2）^-/-和CD11b-DTR转基因小鼠。最后，我们在单核细胞增生性李斯特菌的背景下测试了NAD ⁺对全身免疫应答的生理作用 感染。

结果

我们的体内和体外研究结果表明，施用NAD ⁺后，MCs在无抗原存在且独立于主要APC的情况下仅促进CD4 ⁺ T细胞分化。此外，我们发现MC介导的CD4 ⁺ T细胞分化独立于MHC II和T细胞受体信号传导机制。更重要的是，尽管用NAD ⁺治疗导致CD11c ⁺细胞上MHC II表达降低，但MC介导的CD4 ⁺ T细胞分化使小鼠对致死剂量的L单核细胞增生李斯特菌具有抗性。

结论

总的来说，我们的研究揭示了一条新颖的细胞和分子途径，该途径专门通过MC调节先天性和适应性免疫，并强调了在主要免疫缺陷和抗微生物剂的情况下NAD ⁺的治疗潜力。