Regulation of T cell activation and exhaustion by Tim-3

摘要 跨膜蛋白Tim-3在活化的T细胞的亚群上表达，并且在活化的T细胞中表达。 特别是在所谓的耗尽的T细胞上富集，这与慢性病毒相关。 感染和肿瘤微环境。因此，Tim-3正被积极探索， 肿瘤免疫治疗的潜在靶点。然而，重要的问题仍然是如何 Tim-3表达在急性与慢性感染期间受到调节，以及信号传导如何 Tim-3下游通路调节T细胞功能。使用LCMV感染，我们有 发现Tim-3的表达和信号传导增强了T细胞的早期活化， 但Tim-3与T细胞的发育有关， 疲惫不堪此外，我们还发现转录因子Blimp 1可以控制 Tim-3表达在某些情况下，但不是所有情况下。在这里，我们将进一步定义 Tim-3对塑造整体CD 4+和CD 8 + T细胞对特异性病毒应答的作用 LCMV的表位。我们还将定义Blimp 1的具体要求， 下游因子，包括E-box结合因子抑制剂Id 3。最后我们将 确定通过Tim-3的胞质尾信号传导在调节T细胞中的作用 激活、记忆和衰竭。

Abstract The transmembrane protein Tim-3 is expressed on a subset of activated T cells, and is particularly enriched on so-called exhausted T cells, which are associated with chronic viral infection and the tumor microenvironment. As such, Tim-3 is being actively explored as a potential target for tumor immunotherapy. However, significant questions remain about how Tim-3 expression is regulated during acute vs. chronic infection, and how signaling pathways downstream of Tim-3 modulate T cell function. Using LCMV infection, we have found that Tim-3 expression and signaling augment early T cell activation during both primary and recall responses, but that Tim-3 is dispensable for the development of T cell exhaustion. Furthermore, we have found that the transcription factor Blimp1 can control Tim-3 expression under some, but not all, circumstances. Here we will further define the effects of Tim-3 on sculpting the overall CD4+ and CD8+ T cell responses to specific viral epitopes of LCMV. We will also define the specific requirements for Blimp1 and downstream factors, including the E-box binding factor inhibitor Id3. Finally, we will determine the role of signaling through the cytoplasmic tail of Tim-3 in regulating T cell activation, memory and exhaustion.