Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection

Charlly Kao, Kenneth J. Oestreich, Michael A. Paley, Alison Crawford, Jill M. Angelosanto, Mohammed Alkhatim A. Ali, Andrew M. Intlekofer, Jeremy M. Boss, Steven L. Reiner, Amy S. Weinmann, E. John Wherry

Research output: Contribution to journalArticlepeer-review

389 Scopus citations

Abstract

T cell exhaustion has a major role in failure to control chronic infection. High expression of inhibitory receptors, including PD-1, and the inability to sustain functional T cell responses contribute to exhaustion. However, the transcriptional control of these processes remains unclear. Here we demonstrate that the transcription factor T-bet regulated the exhaustion of CD8+ T cells and the expression of inhibitory receptors. T-bet directly repressed transcription of the gene encoding PD-1 and resulted in lower expression of other inhibitory receptors. Although a greater abundance of T-bet promoted terminal differentiation after acute infection, high T-bet expression sustained exhausted CD8+ T cells and repressed the expression of inhibitory receptors during chronic viral infection. Persistent antigenic stimulation caused downregulation of T-bet, which resulted in more severe exhaustion of CD8+ T cells. Our observations suggest therapeutic opportunities involving higher T-bet expression during chronic infection.

Original languageEnglish
Pages (from-to)663-671
Number of pages9
JournalNature immunology
Volume12
Issue number7
DOIs
StatePublished - May 2011

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