Transcription factor T-beta represses expression
of the inhibitory receptor PD-1 and sustains virus-specific
CD8(+) T cell responses during chronic infection
Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto
JM, Ali MA, Intlekofer AM, Boss JM, Reiner SL, Weinmann
AS, Wherry EJ. (2011) Nat. Immunol. 12:663-671.
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.