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Transcription factor IRF4 Promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection
journal contribution
posted on 2023-05-20, 04:48 authored by Man, K, Gabriel, SS, Liao, Y, Gloury, R, Preston, S, Darren HenstridgeDarren Henstridge, Pellegrini, M, Zehn, D, Berberich-Siebelt, F, Febbraio, MA, Shi, W, Kallies, ADuring chronic stimulation, CD8+ T cells acquire an exhausted phenotype characterized by expression of inhibitory receptors, down-modulation of effector function, and metabolic impairments. T cell exhaustion protects from excessive immunopathology but limits clearance of virus-infected or tumor cells. We transcriptionally profiled antigen-specific T cells from mice infected with lymphocytic choriomeningitis virus strains that cause acute or chronic disease. T cell exhaustion during chronic infection was driven by high amounts of T cell receptor (TCR)-induced transcription factors IRF4, BATF, and NFATc1. These regulators promoted expression of inhibitory receptors, including PD-1, and mediated impaired cellular metabolism. Furthermore, they repressed the expression of TCF1, a transcription factor required for memory T cell differentiation. Reducing IRF4 expression restored the functional and metabolic properties of antigen-specific T cells and promoted memory-like T cell development. These findings indicate that IRF4 functions as a central node in a TCR-responsive transcriptional circuit that establishes and sustains T cell exhaustion during chronic infection. During chronic stimulation, CD8+ T cells acquire an exhausted phenotype characterized by expression of inhibitory receptors, loss of effector function, and metabolic impairments. Man et al. have identified a transcriptional module consisting of the TCR-induced transcription factors IRF4, BATF, and NFATc1 that drives T cell exhaustion and impairs memory T cell development. © 2017
History
Publication title
ImmunityVolume
47Issue
6Pagination
1129-1141ISSN
1074-7613Department/School
School of Health SciencesPublisher
Cell PressPlace of publication
1100 Massachusetts Ave, Cambridge, USA, Ma, 02138Rights statement
Copyright 2017 Crown CopyrightRepository Status
- Restricted