Dissecting Proteostatic Regulation of CD8+ T cell Immunity
Correa, Luis
2024
Abstract
CD8+ T cells are a component of the immune system that are critical to eradicating intracellular pathogens and tumors, as well as providing long-lasting immune protection; however, not all immune responses elicit durable responses leading to loss of protection against infections and malignancy. Though CD8+ T cells markedly upregulate translation and rapidly remodel their proteome during effector differentiation, little is understood about the role proteostasis plays in CD8+ T cell immune responses. Sel1L is a critical component of the endoplasmic reticulum associated degradation (ERAD) complex, facilitating the recognition, retro-translocation of ER misfolded proteins and subsequent proteasomal degradation in the cytosol. Nothing is known about the role of ERAD in CD8+ T cell responses. First, we began by characterizing the experience of ER stress by utilizing in vitro models of T cell activation. Using orthogonal approaches leveraging microscopy, biochemistry and flow cytometry, we uncover that T cells experience transient ER stress in vitro. The ER stress is characterized by misfolded protein accumulation as well as induction of ER stress alleviating pathways such as the unfolded protein response (UPR) and ERAD. In vivo we used murine a model of acute viral infection, lymphocytic choriomeningitis virus Armstrong (LCMV). Utilizing this model, we find that LCMV specific T cells experience ER stress in vivo as well as inducing pathways that alleviate ER stress. These data demonstrate that T cell activation and differentiation is associated with transient ER stress and the induction of ER stress alleviating pathways. Second, to determine how Sel1L/ERAD regulates antigen-specific effector CD8+ T cell survival and function we generated mice with T cells reactive to LCMV that lack Sel1L/ERAD (Sel1LcKO-P14). At baseline Sel1LcKO-P14 cells are comparable to wild-type-P14, with no defects in activation or ER homeostasis. By transferring WT-P14 and Sel1LcKO-P14 in equivalent ratios into mice infected with LCMV, we find that Sel1L is necessary for T cell persistence as the Sel1LcKO-P14 fail to persist. Mechanistically, we find that Sel1LcKO-P14 have reduced oxidative metabolism (OXPHOS) a metabolic program necessary for optimal T cell persistence. To gain insight into how Sel1L regulates T cell metabolism we conducted in vitro studies and find that Sel1L loss is associated with reduction in c-Myc, a central regulator of T cell metabolism, and increased mitochondrial ER contact sites (MERCS). Though the mechanism by which Sel1L regulates c-Myc and the role of MERCS in orchestrating T cell metabolism remain to be fully elucidated these results further demonstrate the connection between the ER and metabolism. Together these findings advance the understanding of pathways regulating T cell persistence. We present these findings in murine systems with correlates in human T cells, they will be significant for future studies aiming to improve the persistence of T cells.Deep Blue DOI
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T cell persistence
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