T-bet represses expression of PD-1 and sustains virus-specific CD8 T cell responses during chronic infection

T cell exhaustion plays a major role in failure to control chronic infections. 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 regulates CD8(+) T cell exhaustion and inhibitory receptor expression. T-bet directly repressed Pdcd1 transcription and decreased the expression of other inhibitory receptors. While elevated T-bet promoted terminal differentiation following acute infection, high T-bet expression sustained exhausted CD8(+) T cells and repressed inhibitory receptor expression during chronic viral infection. Persisting antigenic stimulation caused T-bet downregulation, which resulted in more severe exhaustion of CD8(+) T cells. These observations suggest therapeutic opportunities involving increasing T-bet expression during chronic infection.