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

Research paper by Charlly C Kao, Kenneth J KJ Oestreich, Michael A MA Paley, Alison A Crawford, Jill M JM Angelosanto, Mohammed-Alkhatim A MA Ali, Andrew M AM Intlekofer, Jeremy M JM Boss, Steven L SL Reiner, Amy S AS Weinmann, E John EJ Wherry

Indexed on: 31 May '11Published on: 31 May '11Published in: Nature Immunology



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.