ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection
Luis Correa-Medero, Shayna E Jankowski, Hanna S Hong, Nicholas D Armas, Aditi I Vijendra, Mack B. Reynolds, Garrett M. Fogo, Dominik Awad, Alexander T Dils, Kantaro A Inoki, Reid Williams, AND SHUI QING YE, Nadezhda Svezhova, Francisco Gomez-Rivera, Kathleen L. Collins, Mary X O'Riordan, Thomas H. Sanderson, Costas A. Lyssiotis, Shannon A. Carty
Abstract
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.