Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.
Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.
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DOI：
10.1084/jem.20151467
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发表时间：
2016-07-25
期刊：
影响因子：
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通讯作者：
Tangye SG
中科院分区：
文献类型：
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作者：
Ma CS;Wong N;Rao G;Nguyen A;Avery DT;Payne K;Torpy J;O'Young P;Deenick E;Bustamante J;Puel A;Okada S;Kobayashi M;Martinez-Barricarte R;Elliott M;Sebnem Kilic S;El Baghdadi J;Minegishi Y;Bousfiha A;Robertson N;Hambleton S;Arkwright PD;French M;Blincoe AK;Hsu P;Campbell DE;Stormon MO;Wong M;Adelstein S;Fulcher DA;Cook MC;Stepensky P;Boztug K;Beier R;Ikincioğullari A;Ziegler JB;Gray P;Picard C;Boisson-Dupuis S;Phan TG;Grimbacher B;Warnatz K;Holland SM;Uzel G;Casanova JL;Tangye SG
唐野和他的合作者使用一系列突变体来阐明产生不同的人类效应CD4+T细胞亚群所需的途径。幼稚的CD4+T细胞分化为特定的效应亚群-Th1、Th2、Th17和T滤泡辅助细胞(TFH)-提供对病原体感染的免疫力。产生这些效应细胞所涉及的信号通路是部分已知的。然而，人类初级免疫缺陷潜在的突变对这些过程的影响，以及它们如何损害特定的免疫反应，仍然没有解决。通过对关键信号通路突变个体的研究，我们确定了在体外调节人类CD4+T细胞分化的非冗余通路。IL-12Rβ1/TYK2和干扰素-γR/STAT1在前馈环路中诱导Th1细胞，而IL-21/IL-21R/STAT3信号是Th17、Tfh和IL-10分泌细胞所必需的。IL-12R、β-1/TYK-2和NEMO也是Th17诱导所必需的。值得注意的是，功能增益STAT1突变概括了显性阴性STAT3突变对Tfh和Th17细胞的影响，揭示了多态STAT1对STAT3的假定抑制作用。这些发现提供了对人类T细胞效应器功能要求的机械洞察，并解释了这些免疫缺陷疾病的临床表现。此外，他们确定了在感染、接种疫苗或免疫失调的情况下，可以针对调节CD4+T细胞效应器功能的分子。
Tangye and collaborators use a series of mutants to elucidate the pathways required to generate distinct subsets of human effector CD4+ T cells. Naive CD4+ T cells differentiate into specific effector subsets—Th1, Th2, Th17, and T follicular helper (Tfh)—that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4+ T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10–secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4+ T cell effector function in the settings of infection, vaccination, or immune dysregulation.