The CD8+ T cell tolerance checkpoint triggers a distinct differentiation state defined by protein translation defects
Details
Publication Year 2024-06-11,Volume 57,Issue #6,Page 1324-1344
Journal Title
Immunity
Publication Type
Research article
Abstract
Peripheral CD8(+) T cell tolerance is a checkpoint in both autoimmune disease and anti-cancer immunity. Despite its importance, the relationship between tolerance-induced states and other CD8(+) T cell differentiation states remains unclear. Using flow cytometric phenotyping, single-cell RNA sequencing (scRNA-seq), and chromatin accessibility profiling, we demonstrated that in vivo peripheral tolerance to a self-antigen triggered a fundamentally distinct differentiation state separate from exhaustion, memory, and functional effector cells but analogous to cells defectively primed against tumors. Tolerant cells diverged early and progressively from effector cells, adopting a transcriptionally and epigenetically distinct state within 60 h of antigen encounter. Breaching tolerance required the synergistic actions of strong T cell receptor (TCR) signaling and inflammation, which cooperatively induced gene modules that enhanced protein translation. Weak TCR signaling during bystander infection failed to breach tolerance due to the uncoupling of effector gene expression from protein translation. Thus, tolerance engages a distinct differentiation trajectory enforced by protein translation defects.
Publisher
Cell Press
Keywords
*CD8-Positive T-Lymphocytes/immunology; Animals; *Cell Differentiation/immunology; Mice; *Receptors, Antigen, T-Cell/metabolism/immunology; *Immune Tolerance/immunology; *Protein Biosynthesis/immunology; Signal Transduction/immunology; Mice, Inbred C57BL; Autoantigens/immunology; CD8(+) T cell; autoimmunity; cancer; differentiation; dysfunction; effector T cell; exhaustion; immunotherapy; stem-like T cell; tolerance
Department(s)
Laboratory Research
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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