ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection
The maintenance and persistence of antigen-specific CD8+ T cells underlies the efficacy of vaccines and immunotherapies. Pathways that contribute to the loss of CD8+ T cells are not completely understood. Uncovering the pathways underlying the limited persistence of CD8+ T cells would be of significant benefit for developing novel strategies of promoting T cell persistence and identifying patients whose T cells could function best for treatment. Here, we demonstrate the experience of endoplasmic reticulum (ER) stress in differentiating murine CD8+ T cells in vitro and in vivo. ER-associated degradation (ERAD) adapter Sel1L was found to be selectively induced in activated CD8+ T cells. Loss of Sel1L limited CD8+ T cell function and memory formation following acute viral infection. Mechanistically, Sel1L is required for optimal T cell oxidative metabolism and mitochondrial fusion. Finally, we demonstrate that human CD8+ T cells experience ER stress after activation and that ER stress is negatively associated with improved T cell functionality in bispecific antibody therapy and chimeric antigen receptor T cell therapy. Together these results demonstrated that ER stress and ERAD are important and novel regulators of T cell function and persistence. Overall design: WT and Sel1LcKO P14 were sorted from LCMV-Armstrong infected host at D8 post infection and RNA-seq was conducted