Abstract
CD8+ T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'1. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1)2,3, that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling4,5. It is not known whether PD-1 also acts by upregulating genes in exhausted T cells that impair their function. Here we analyzed gene expression profiles from HIV-specific CD8+ T cells in individuals with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8+ T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD-1 inhibition. Silencing BATF in T cells from individuals with chronic viremia rescued HIV-specific T cell function. Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes—such as BATF—that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV.
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Acknowledgements
We would like to thank the subjects for taking part in the study; E. Cutrell, B. Baker, K. Moss, A. Rathod and C. Brume for coordinating sample management; and A. Sharpe, T. Golub, G. Lauer, M. Altfeld and H. Joffe for valuable discussions. This work was supported by US National Institutes of Health grants AI082630, AI56299, HHSN26620050030C and HL092565, the International HIV Controllers Study and the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative.
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M.Q. designed and performed experiments, analyzed data and helped write the paper. F. Pereyra designed the clinical components of the study. B.N. and J.L.J. designed and performed computational experiments. F. Porichis, D.S.K., J.Z. and D.E.K. designed and performed siRNA experiments in samples from subjects with HIV. C.F., Q.E., B.J., K.B., S.I., K.R., I.T., A.P.-T., D.D. and L.F. all performed experiments. G.J.F. designed experiments and developed PD-L1–Ig. J.A., A.C., H.S. and E.J.W. designed and performed mouse experiments and analyzed data. W.N.H., B.E. and B.D.W. conceived of the study and designed the experiments. W.N.H. analyzed data and wrote the paper.
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Quigley, M., Pereyra, F., Nilsson, B. et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med 16, 1147–1151 (2010). https://doi.org/10.1038/nm.2232
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DOI: https://doi.org/10.1038/nm.2232
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