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S1P(1)-mTOR 轴指导 TH1 和 Treg 细胞的相互分化。

The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells.

机构信息

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

出版信息

Nat Immunol. 2010 Nov;11(11):1047-56. doi: 10.1038/ni.1939. Epub 2010 Sep 19.

DOI:10.1038/ni.1939
PMID:20852647
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2958252/
Abstract

Naive CD4(+) T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. Here we found that the differentiation of proinflammatory T helper type 1 (T(H)1) cells and anti-inflammatory Foxp3(+) regulatory T cells (T(reg) cells) was reciprocally regulated by S1P(1), a receptor for the bioactive lipid sphingosine 1-phosphate (S1P). S1P(1) inhibited the generation of extrathymic and natural T(reg) cells while driving T(H)1 development in a reciprocal manner and disrupted immune homeostasis. S1P(1) signaled through the kinase mTOR and antagonized the function of transforming growth factor-β mainly by attenuating sustained activity of the signal transducer Smad3. S1P(1) function was dependent on endogenous sphingosine kinase activity. Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same S1P(1) and mTOR pathway to regulate the dichotomy between T(H)1 cells and T(reg) cells. Our studies establish an S1P(1)-mTOR axis that controls T cell lineage specification.

摘要

幼稚 CD4(+)T 细胞分化为多种效应和调节谱系，以协调免疫和耐受。在这里，我们发现促炎 T 辅助细胞 1 型（T(H)1）和抗炎 Foxp3(+)调节性 T 细胞（T(reg)细胞）的分化受到鞘氨醇 1-磷酸（S1P）的受体 S1P(1)的反向调节，S1P 是生物活性脂质。S1P(1)以相反的方式抑制胸腺外和天然 T(reg)细胞的产生，同时驱动 T(H)1 发育，并破坏免疫稳态。S1P(1)通过激酶 mTOR 信号转导，主要通过减弱信号转导子 Smad3 的持续活性来拮抗转化生长因子-β的功能。S1P(1)的功能依赖于内源性鞘氨醇激酶活性。值得注意的是，两种看似不相关的免疫抑制剂，FTY720 和雷帕霉素，靶向相同的 S1P(1)和 mTOR 途径，以调节 T(H)1 细胞和 T(reg)细胞之间的二分法。我们的研究确立了 S1P(1)-mTOR 轴，该轴控制 T 细胞谱系特异性。

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