Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14152-7. doi: 10.1073/pnas.1119744109. Epub 2012 Aug 13.
T-cell anergy is a state of T cells that is hyporesponsive to stimulation via the T-cell receptor and costimulatory molecules and is thought to be important for self-tolerance. How T-cell anergy is regulated is still poorly understood. We report here that tuberous sclerosis (TSC)1 is critical for T-cell anergy. Deficiency of TSC1 resulted in enhanced T-cell proliferation and cytokine production in the absence of cluster of differentiation (CD)28-mediated costimulation, accompanied by enhanced T-cell metabolism. Resistance of TSC1-deficient T cells to anergy is correlated with increased signaling through the mammalian target of rapamycin complex (mTORC)1 and can be reverted by treatment of these cells with mTORC1 inhibitor rapamycin. Expression of the inducible costimulator (ICOS) is increased in TSC1-deficient T cells, which can be inhibited by rapamycin. Simultaneous blockade of both CD28 and ICOS costimulation partially restored sensitivity of TSC1-deficient T cells to anergy induction. Together, our data indicate that TSC1 is crucial for T-cell anergy by inhibiting mTORC1 signaling through both ICOS-dependent and -independent mechanisms.
T 细胞失能是 T 细胞的一种状态，其对 T 细胞受体和共刺激分子的刺激反应迟钝，被认为对自身耐受很重要。T 细胞失能如何调节仍知之甚少。我们在这里报告，结节性硬化症（TSC）1 对 T 细胞失能至关重要。TSC1 缺乏导致在没有 CD28 介导的共刺激的情况下增强了 T 细胞的增殖和细胞因子的产生，同时增强了 T 细胞的代谢。TSC1 缺陷型 T 细胞对失能的抗性与通过雷帕霉素（mTORC1 的抑制剂）治疗这些细胞可逆转的哺乳动物靶标复合物（mTORC）1 的信号转导增加相关。在 TSC1 缺陷型 T 细胞中诱导共刺激物（ICOS）的表达增加，雷帕霉素可抑制其表达。同时阻断 CD28 和 ICOS 共刺激部分恢复了 TSC1 缺陷型 T 细胞对失能诱导的敏感性。总之，我们的数据表明 TSC1 通过 ICOS 依赖和非依赖的机制抑制 mTORC1 信号转导，对 T 细胞失能至关重要。
