Journal article

Transcription Factor IRF4 Promotes CD8( ) T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection

Kevin Man, Sarah S Gabriel, Yang Liao, Renee Gloury, Simon Preston, Darren C Henstridge, Marc Pellegrini, Dietmar Zehn, Friederike Berberich-Siebelt, Mark A Febbraio, Wei Shi, Axel Kallies

IMMUNITY | CELL PRESS | Published : 2017


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 mediate..

View full abstract


Awarded by National Health and Medical Research Council of Australia

Awarded by Fritz Thyssen Stiftung

Awarded by Wilhelm Sander-Stiftung

Funding Acknowledgements

We wish to thank Liana Mackiewicz, Carolina Alvarado, and Benjamin Lunz for expert technical support, and Stephen Nutt, Edgar Serfling, and Stefan Klein-Hessling for scientific discussion. We thank Anjana Rao, Laurie Glimcher, Pamela Ohashi, Tak Mak, Ulf Klein, Mark Chong, and Daniel Gray for mice. This work was supported by grants and fellowships from the National Health and Medical Research Council of Australia (project grants 1032850 and 1085151 to A.K., 1006592, 1045549, and 1065626 to M.P., 1023454 to W.S., Senior Research Fellowship 1021168 and Senior Principal Research Fellowship 1116936 to M.A.F.), the Walter and Eliza Hall Institute Centenary Fellowship funded by CSL (to W.S.), the Swiss National Science Foundation and the Novartis Foundation for Medical-Biological Research (fellowships to S.S.G.), and the Sylvia and Charles Viertel Foundation (Senior Medical Research Fellowships to A.K. and M.P.). Further funding was provided by the Fritz Thyssen Stiftung ( and the Wilhelm Sander-Stiftung (2012.047.1) to F.B.-S. This study was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support scheme.