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Transcription factor IRF4 Promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection
Citation
Man, K and Gabriel, SS and Liao, Y and Gloury, R and Preston, S and Henstridge, DC and Pellegrini, M and Zehn, D and Berberich-Siebelt, F and Febbraio, MA and Shi, W and Kallies, A, Transcription factor IRF4 Promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection, Immunity, 47, (6) pp. 1129-1141. ISSN 1074-7613 (2017) [Refereed Article]
Copyright Statement
Copyright 2017 Crown Copyright
DOI: doi:10.1016/j.immuni.2017.11.021
Abstract
During 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
Item Details
| Item Type: | Refereed Article |
|---|---|
| Keywords: | BATF, CD8+, chronic infection, differentiation, exhaustion, IRF4, memory, metabolic function, NAICE, NFAT, NFAT AP-1 IRF4 composite element, TCF1, transcription, transcription factor, animal cell |
| Research Division: | Biological Sciences |
| Research Group: | Biochemistry and cell biology |
| Research Field: | Cell metabolism |
| Objective Division: | Health |
| Objective Group: | Clinical health |
| Objective Field: | Clinical health not elsewhere classified |
| UTAS Author: | Henstridge, DC (Dr Darren Henstridge) |
| ID Code: | 133374 |
| Year Published: | 2017 |
| Web of Science® Times Cited: | 191 |
| Deposited By: | Health Sciences |
| Deposited On: | 2019-06-24 |
| Last Modified: | 2022-08-25 |
| Downloads: | 0 |
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