Transcription Factor IRF4 Promotes CD8(+) T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection
- Author(s)
- Man, K; Gabriel, SS; Liao, Y; Gloury, R; Preston, S; Henstridge, DC; Pellegrini, M; Zehn, D; Berberich-Siebelt, F; Febbraio, MA; Shi, W; Kallies, A;
- Details
- Publication Year 2017-12-19,Volume 47,Issue #6,Page 1129-1141 e5
- Journal Title
- Immunity
- Publication Type
- Journal Article
- 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.
- Publisher
- Cell Press
- Research Division(s)
- Molecular Immunology; Bioinformatics; Infection And Immunity
- PubMed ID
- 29246443
- Publisher's Version
- https://doi.org/10.1016/j.immuni.2017.11.021
- NHMRC Grants
- NHMRC/1032850, NHMRC/1085151, NHMRC/1006592, NHMRC/1065626, NHMRC/1045549, NHMRC/1021168,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-01-15 12:39:55
Last Modified: 2018-02-14 03:59:23