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.
['Man|Kevin|K|', 'Gabriel|Sarah S|SS|', 'Liao|Yang|Y|', 'Gloury|Renee|R|', 'Preston|Simon|S|', 'Henstridge|Darren C|DC|', 'Pellegrini|Marc|M|', 'Zehn|Dietmar|D|', 'Berberich-Siebelt|Friederike|F|', 'Febbraio|Mark A|MA|', 'Shi|Wei|W|', 'Kallies|Axel|A|']
D000818:Animals D050976:Basic-Leucine Zipper Transcription Factors D018414:CD8-Positive T-Lymphocytes D002454:Cell Differentiation D005786:Gene Expression Regulation D057809:HEK293 Cells D051538:Hepatocyte Nuclear Factor 1-alpha D006801:Humans D007156:Immunologic Memory D050835:Interferon Regulatory Factors D008213:Lymphocyte Activation D008212:Lymphocyte Depletion D008216:Lymphocytic Choriomeningitis D008217:Lymphocytic choriomeningitis virus D051379:Mice D018345:Mice, Knockout D050778:NFATC Transcription Factors D061026:Programmed Cell Death 1 Receptor D011948:Receptors, Antigen, T-Cell D015398:Signal Transduction
transcription IRF4 exhaustion chronic infection BATF TCF1 memory differentiation CD8(+) NAICE NFAT NFAT_AP-1_IRF4 composite element metabolic function