Lee Seung-Joo, Rossi Robert J, Lee Sun-Kyeong, Croft Michael, Kwon Byoung S, Mittler Robert S, Vella Anthony T
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
J Immunol. 2007 Aug 15;179(4):2203-14. doi: 10.4049/jimmunol.179.4.2203.
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-7Ralpha-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-7Ralpha 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.
肿瘤坏死因子受体（TNFR）超家族成员4-1BB（CD137）和OX40（CD134）是共刺激分子，可有效增强CD8和CD4 T细胞反应。同时给予激动型抗CD137和抗CD134单克隆抗体进行治疗，可介导已形成肿瘤的排斥反应，并促进强大的CD8 T细胞反应。为揭示其机制，研究发现特定CD8 T细胞表达CD137对于效应细胞的最佳克隆扩增和积累至关重要。尽管如此，当特定T细胞或宿主单独表达CD137时，双重共刺激可诱导产生超效应CD8 T细胞。也许令人惊讶的是，完全缺乏CD137会阻止抗CD134增强超效应分化，这表明这些相关途径之间存在未被认识的联系。最终推断，这些强大的双重共刺激反应涉及常见的γ家族成员，并且我们发现特定CD8 T细胞的CD25和IL-7Rα链表达大幅增加。为进一步研究，结果表明IL-7介导T细胞积累，但重要的是，生存的逐渐和优先效应针对超效应CD8 T细胞。事实上，效应分化的明显增强与特定CD8 T细胞IL-7Rα表达量的增加成正比。因此，通过CD137和CD134的双重共刺激通过一条独特的IL-7依赖性途径驱动超效应CD8 T细胞的产生和存活。
