ER-associated degradation adapter Sel1L is required for CD8⁺ T cell function and memory formation following acute...

The maintenance of antigen-specific CD8⁺ T cells underlies the efficacy of vaccines and immunotherapies. Pathways contributing to CD8⁺ T cell loss 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. Here, we demonstrate that murine CD8⁺ T cells experience endoplasmic reticulum (ER) stress following activation and that the ER-associated degradation (ERAD) adapter Sel1L is induced in activated CD8⁺ T cells. Sel1L loss limits CD8⁺ T cell function and memory formation following acute viral infection. Mechanistically, Sel1L is required for optimal bioenergetics and c-Myc expression. Finally, we demonstrate that human CD8⁺ T cells experience ER stress upon activation and that ER stress is negatively associated with improved T cell functionality in T cell-redirecting therapies. Together, these results demonstrate that ER stress and ERAD are important regulators of T cell function and persistence.