Basis of CTLA-4 function in regulatory and conventional CD4+ T cells
Basis of CTLA-4 function in regulatory and conventional CD4+ T cells
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DOI：
10.1182/blood-2011-11-388918
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发表时间：
2012-05-31
期刊：
影响因子：
20.3
通讯作者：
Singer, Alfred
中科院分区：
文献类型：
--
作者：
Tai, Xuguang;Van Laethem, Francois;Singer, Alfred
CTLA-4蛋白有助于调节性T细胞（Tcells）的抑制功能，但它们这样做的机制仍不完全清楚。在本研究中，我们评估了CTLA-4蛋白在Tconv和常规（Tconv）CD 4（+）T细胞中的功能。我们报道CTLA-4蛋白负责所有3种特征性Treg功能，即抑制、TCR低信号和无反应性。然而，Treg抑制和无反应性仅需要CTLA-4的外部结构域，而TCR低信号需要其内部结构域。令人惊讶的是，TCR低信号既不是Treg抑制所需的，也不是无反应性所需的，因为CTLA-4的外部结构域的共刺激阻断足以实现这两种功能。我们还报告说，CTLA-4蛋白定位在Tconv的膜下囊泡，迅速回收到/从细胞表面，而在幼稚Tconv细胞中的CTLA-4蛋白保留在高尔基体囊泡远离细胞膜，并没有影响Tconv细胞功能。然而，Tconv细胞的TCR信号从高尔基体滞留释放CTLA-4蛋白，并导致活化的Tconv细胞获得抑制功能。因此，本研究的结果证明了CTLA-4蛋白功能的细胞内定位的重要性，并揭示了CTLA-4蛋白外化赋予调节性和常规CD 4（+）T细胞抑制剂功能。（血。2012; 119（22）：5155-5163）
CTLA-4 proteins contribute to the suppressor function of regulatory T cells (Tregs), but the mechanism by which they do so remains incompletely understood. In the present study, we assessed CTLA-4 protein function in both Tregs and conventional (Tconv) CD4(+) T cells. We report that CTLA-4 proteins are responsible for all 3 characteristic Treg functions of suppression, TCR hyposignaling, and anergy. However, Treg suppression and anergy only required the external domain of CTLA-4, whereas TCR hyposignaling required its internal domain. Surprisingly, TCR hyposignaling was neither required for Treg suppression nor anergy because costimulatory blockade by the external domain of CTLA-4 was sufficient for both functions. We also report that CTLA-4 proteins were localized in Tregs in sub-membrane vesicles that rapidly recycled to/from the cell surface, whereas CTLA-4 proteins in naive Tconv cells were retained in Golgi vesicles away from the cell membrane and had no effect on Tconv cell function. However, TCR signaling of Tconv cells released CTLA-4 proteins from Golgi retention and caused activated Tconv cells to acquire suppressor function. Therefore, the results of this study demonstrate the importance of intracellular localization for CTLA-4 protein function and reveal that CTLA-4 protein externalization imparts suppressor function to both regulatory and conventional CD4(+) T cells. (Blood. 2012; 119(22): 5155-5163)