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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

Nature Immunology volume 12, pages 663–671 (2011)Cite this article

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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.

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Figure 1: Downregulation of T-bet during chronic relative to its expression during acute LCMV infection.
Figure 2: Ablation of T-bet results in loss of antigen-specific CD8+ T cells and impairs viral control during chronic infection.
Figure 3: Ablation of T-bet impairs the function of antigen-specific CD8+ T cells later but not early during chronic infection.
Figure 4: Inverse correlation of the expression of T-bet and PD-1 during chronic infection.
Figure 5: Downregulation of T-bet during chronic infection is due to persistent antigen.
Figure 6: Cell-intrinsic role for T-bet in the repression of PD-1, demonstrated by peripheral chimeras and mixed transfer of P14 cells.
Figure 7: T-bet overexpression downregulates PD-1 expression and improves the durability of exhausted antigen-specific CD8+ T cells.
Figure 8: T-bet regulates the expression of many cell-surface inhibitory receptors during chronic infection.
Figure 9: T-bet is a direct transcriptional repressor of the Pdcd1.

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Acknowledgements

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.).

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Authors and Affiliations

  1. Department of Microbiology and Institute for Immunology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Charlly Kao, Michael A Paley, Alison Crawford, Jill M Angelosanto, Mohammed-Alkhatim A Ali & E John Wherry

  2. Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA

    Kenneth J Oestreich & Amy S Weinmann

  3. Department of Medicine and Institute for Immunology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Andrew M Intlekofer & Steven L Reiner

  4. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA

    Jeremy M Boss

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Contributions

C.K. and E.J.W. designed the experiments and analyzed the data; K.J.O. did ChIP for CD4+ T cells and EL4 luciferase assays; A.C., J.M.A., M.A.P., M.-A.A., and A.M.I. assisted in doing and analyzing experiments; J.M.B., S.L.R. and A.S.W. assisted with the design of the experiments and provided constructs, reagents and mouse strains; and C.K. and E.J.W. wrote the manuscript.

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Correspondence to E John Wherry.

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E.J.W. has a patent licensing agreement on the PD-1 pathway.

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Kao, C., Oestreich, K., Paley, M. et al. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol 12, 663–671 (2011). https://doi.org/10.1038/ni.2046

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