The role for ER associated degradation (ERAD) in T cell homeostasis and memory

项目摘要 CD 8 + T细胞对于根除病毒感染和肿瘤至关重要， 持久的保护;然而，并非所有的免疫应答都能引起功能性和持久的免疫应答。 导致丧失对细胞内病原体和癌症的保护的反应。有效的T 细胞免疫需要严格的控制，以维持细胞间的适当平衡。 静止、活化和细胞死亡。优雅的工作已经完成，以阐明 转录、表观遗传和代谢网络来调节T细胞。相比之下， 已知细胞蛋白质稳态（蛋白质稳态）如何调节CD 8 + T细胞命运。 蛋白质稳态主要通过内质网相关的降解来维持 （ERAD）和未折叠蛋白反应（UPR）途径。ERAD复合物识别错误折叠 ER中的蛋白质，并将它们转运到胞质溶胶中进行蛋白酶体降解。S1 L是一个 ERAD复合物的关键组成部分，促进识别，逆向易位和 ER中错误折叠蛋白的后续蛋白酶体降解。虽然， UPR已在T细胞应答中进行了研究，但尚不清楚Sel 1 L/ERAD如何控制CD 8 + T细胞应答。 细胞命运最近，我们在小鼠T细胞中使用Se 11 L的条件性缺失来破坏ERAD， 确定了ERAD在T细胞静止和稳态存活中的新作用。的额外 初步结果表明，抗原特异性CD 8 + T细胞经历动态ER， 急性病毒感染期间的应激和Sel 1 L是保护抗原特异性CD 8 + T细胞所必需的 以细胞内在的方式从病毒感染后的细胞死亡中恢复。我们的长期目标是确定 调节T细胞命运的分子机制，并发现新的治疗靶点， 用于调节人T细胞对感染和肿瘤的应答。的目标 本研究旨在剖析Sel 1 L/ERAD如何在稳态下调节CD 8 + T细胞的命运， 感染后。我们的中心假设是，Sel 1 L/ERAD是维持细胞增殖所必需的。 在体内平衡期间和抗原活化后，CD 8 + T细胞中的蛋白质平衡。来测试我们 中心假设，我们将追求以下目标：1）确定Sel 1 L/ERAD如何 调节CD 8 + T细胞的稳态和2）剖析Sel 1 L/ERAD的机制， 在抗原活化后保留CD 8 + T细胞。在本建议中，我们将确定如何 Sel 1 L/ERAD保护幼稚和活化的CD 8 + T细胞对抗失调的蛋白质稳态， 不适当的UPR激活和改变的细胞代谢。这些目标的实现将 导致知识，有可能提供新的治疗目标，可以提高T 细胞对病毒感染的反应，并提高保护性疫苗的反应。

PROJECT SUMMARY CD8+ T cells are critical to eradicate viral infections and tumors, as well as providing long-lasting protection; however, not all immune responses elicit functional and durable immune responses leading to loss of protection against intracellular pathogens and cancer. Effective T cell immunity requires tight control to maintain the appropriate equilibrium between cellular quiescence, activation and cell death. Elegant work has been done to elucidate the transcriptional, epigenetic and metabolic networks that regulate T cells. In contrast, much less is known about how cellular protein homeostasis (proteostasis) regulates CD8+ T cell fate. Proteostasis is maintained primarily through the endoplasmic reticulum associated degradation (ERAD) and unfolded protein response (UPR) pathways. ERAD complexes recognize misfolded proteins in ER and translocate them into the cytosol for proteasomal degradation. Sel1L is a critical component of the ERAD complex, facilitating the recognition, retro-translocation and subsequent proteasomal degradation of misfolded proteins in the ER. Though the role of the UPR has been studied in T cell responses, nothing is known how Sel1L/ERAD controls CD8+ T cell fate. Using conditional deletion of Se1lL in murine T cells to disrupt ERAD, we recently identified a novel role for ERAD in T cell quiescence and survival at steady-state. In additional preliminary results, we demonstrate that antigen-specific CD8+ T cells experience dynamic ER stress during acute viral infection and Sel1L is required to protect antigen-specific CD8+ T cells in a cell-intrinsic manner from cell death following viral infection. Our long-term goal is to identify molecular mechanisms that regulate T cell fates and discover novel therapeutic targets that can be used to modulate human T cell responses against infections and tumors. The objective of this proposal is to dissect how Sel1L/ERAD regulates CD8+ T cell fate at steady-state and following infection. Our central hypothesis is that Sel1L/ERAD is required to maintain cellular proteostasis in CD8+ T cells during homeostasis and following antigen activation. To test our central hypothesis, we will pursue the following aims: 1) to determine how Sel1L/ERAD regulates CD8+ T cell homeostasis and 2) to dissect the mechanisms by which Sel1L/ERAD preserves CD8+ T cells following antigen activation. In this proposal, we will identify how Sel1L/ERAD protects naïve and activated CD8+ T cells against dysregulated proteostasis, inappropriate UPR activation and altered cellular metabolism. The completion of these aims will lead to knowledge that has the potential for offering new therapeutic targets that can enhance T cell responses to viral infections and improve protective vaccines responses.