TY - JOUR
T1 - Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection
AU - Kao, Charlly
AU - Oestreich, Kenneth J.
AU - Paley, Michael A.
AU - Crawford, Alison
AU - Angelosanto, Jill M.
AU - Ali, Mohammed Alkhatim A.
AU - Intlekofer, Andrew M.
AU - Boss, Jeremy M.
AU - Reiner, Steven L.
AU - Weinmann, Amy S.
AU - Wherry, E. John
N1 - Funding Information:
We thank W. Pear (University of Pennsylvania) for human embryonic kidney 293T cells; members of the Wherry and Reiner laboratories as well as M.R. Betts for comments and insights; and N. Cereb, S.Y. Yang and L. Boring for assistance with construction of loxP-flanked Tbx21. Supported by the US National Institutes of Health (AI007518 to C.K.; AI071309, AI082630, AI083022, AI078897 and HHSN266200500030C to E.J.W.; and AI061699 and AI076458 to S.L.R.), the Foundation for the National Institutes of Health and Grand Challenge in Global Health (E.J.W.) and the Dana Foundation (E.J.W.).
PY - 2011/5
Y1 - 2011/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79959375167&partnerID=8YFLogxK
U2 - 10.1038/ni.2046
DO - 10.1038/ni.2046
M3 - Article
C2 - 21623380
AN - SCOPUS:79959375167
SN - 1529-2908
VL - 12
SP - 663
EP - 671
JO - Nature immunology
JF - Nature immunology
IS - 7
ER -