Transcription Factor IRF4 Promotes CD8(+) T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection
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.
|ISBN||1097-4180 (Electronic) 1074-7613 (Linking)|
|Authors||Man, K.; Gabriel, S. S.; Liao, Y.; Gloury, R.; Preston, S.; Henstridge, D. C.; Pellegrini, M.; Zehn, D.; Berberich-Siebelt, F.; Febbraio, M. A.; Shi, W.; Kallies, A.|
|Responsible Garvan Author|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/29246443|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/14470|