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

Abstract

The maintenance of antigen-specific CD8+ Tcells underlies the efficacy of vaccines and immunotherapies. Pathways contributing to CD8+ Tcell loss are not completely understood. Uncovering the pathways underlying the limited persistence of CD8+ Tcells would be of significant benefit for developing novel strategies of promoting Tcell persistence. Here, we demonstrate that murine CD8+ Tcells experience endoplasmic reticulum (ER) stress following activation and that the ER-associated degradation (ERAD) adapter Sel1L is induced in activated CD8+ Tcells. Sel1L loss limits CD8+ Tcell 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+ Tcells experience ER stress upon activation and that ER stress is negatively associated with improved Tcell functionality in Tcell-redirecting therapies. Together, these results demonstrate that ER stress and ERAD are important regulators of Tcell function and persistence.