CD134 costimulation couples the CD137 pathway to induce production of supereffector CD8 T cells that become IL-7 dependent
CD134 costimulation couples the CD137 pathway to induce production of supereffector CD8 T cells that become IL-7 dependent
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DOI：
10.4049/jimmunol.179.4.2203
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Vella, Anthony T.
中科院分区：
文献类型：
--
作者：
Lee, Seung-Joo;Rossi, Robert J.;Vella, Anthony T.
TNFR超家族成员4-1BB(CD137)和OX40(CD134)是共刺激分子，可以有效地增强CD8和CD4T细胞的反应。同时给予激动剂抗CD137和-CD134单抗治疗，可介导已建立的肿瘤的排斥反应，并促进强大的CD8 T细胞反应。为了揭示这一机制，特定CD8T细胞表达CD137的作用被确定为最佳的克隆扩增和效应细胞积累所必需的。然而，当特定的T细胞或宿主单独携带CD137时，双重共刺激诱导超级效应CD8T细胞的产生。也许令人惊讶的是，CD137的完全缺失阻止了超级效应器分化的抗CD134增强，显示了这些相关途径之间的不为人知的联系。最终，我们推测这些强大的双重共刺激反应涉及常见的伽马家族成员，我们发现特定的CD8 T细胞显著增加了CD25和IL-7Rα链的表达。为了进一步研究这一点，研究表明，IL-7介导了T细胞的聚集，但重要的是，超效应CD8 T细胞具有逐渐和优先的生存效应。事实上，效应器分化的明显增强与特定CD8T细胞表达IL-7Rα的增加成正比。因此，通过CD137和CD134的双重共刺激通过不同的IL-7依赖途径来驱动超级效应器CD8T细胞的产生和存活。
The TNFR superfamily members 4-1BB (CD137) and OX40 (CD134) are costimulatory molecules that potently boost CD8 and CD4 T cell responses. Concomitant therapeutic administration of agonist anti-CD137 and -CD134 mAbs mediates rejection of established tumors and fosters powerful CD8 T cell responses. To reveal the mechanism, the role of CD137 expression by specific CD8 T cells was determined to be essential for optimal clonal expansion and accumulation of effector cells. Nonetheless, dual costimulation induced production of supereffector CD8 T cells when either the specific T cells or the host alone bore CD137. Perhaps surprisingly, the total absence of CD137 prevented anti-CD134 augmentation of supereffector differentiation demonstrating an unappreciated link between these related pathways. Ultimately, it was reasoned that these powerful dual costimulatory responses involved common gamma family members, and we show substantial increases of CD25 and IL-7R alpha-chain expression by the specific CD8 T cells. To investigate this further, it was shown that IL-7 mediated T cell accumulation, but importantly, a gradual and preferential effect of survival was directed toward supereffector CD8 T cells. In fact, a clear enhancement of effector differentiation was demonstrated to be proportional to the increasing amount of IL-7R alpha expression by the specific CD8 T cells. Therefore, dual costimulation through CD137 and CD134 drives production and survival of supereffector CD8 T cells through a distinct IL-7-dependent pathway.