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.