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

Luis O 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 G Williams; Annabelle M Ye; Nadezhda Svezhova; Francisco Gomez-Rivera; Kathleen L Collins; Mary X O'Riordan; Thomas H Sanderson; Costas A Lyssiotis; Shannon A Carty

doi:10.1016/j.celrep.2024.114156

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

Cell Rep. 2024 Apr 29;43(5):114156. doi: 10.1016/j.celrep.2024.114156. Online ahead of print.

Authors

Luis O Correa-Medero¹, Shayna E Jankowski², Hanna S Hong¹, Nicholas D Armas¹, Aditi I Vijendra², Mack B Reynolds¹, Garrett M Fogo³, Dominik Awad⁴, Alexander T Dils⁵, Kantaro A Inoki², Reid G Williams¹, Annabelle M Ye², Nadezhda Svezhova⁶, Francisco Gomez-Rivera¹, Kathleen L Collins⁷, Mary X O'Riordan⁸, Thomas H Sanderson⁹, Costas A Lyssiotis¹⁰, Shannon A Carty¹¹

Affiliations

¹ Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
² University of Michigan, Ann Arbor, MI 48109, USA.
³ Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁴ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
⁷ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
⁹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
¹⁰ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: scarty@umich.edu.

PMID: 38687642
DOI: 10.1016/j.celrep.2024.114156

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.

Keywords: CD8 T cell; CP: Immunology; ER stress; ERAD; Myc; T cell memory; immunometabolism; protein homeostasis.

Abstract

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