Abstract
The engagement of programmed death 1 (PD-1) to its ligands, PD-L1 and PD-L21,2,3,4, inhibits proliferation and cytokine production mediated by antibodies to CD3 (refs. 5,6,7). Blocking the PD-1–PD-L1 pathway in mice chronically infected with lymphocytic choriomeningitis virus restores the capacity of exhausted CD8+ T cells to undergo proliferation, cytokine production and cytotoxic activity and, consequently, results in reduced viral load8. During chronic HIV infection, HIV-specific CD8+ T cells are functionally impaired9,10,11, showing a reduced capacity to produce cytokines and effector molecules as well as an impaired capacity to proliferate12,13,14,15. Here, we found that PD-1 was upregulated on HIV-specific CD8+ T cells; PD-1 expression levels were significantly correlated both with viral load and with the reduced capacity for cytokine production and proliferation of HIV-specific CD8+ T cells. Notably, cytomegalovirus (CMV)-specific CD8+ T cells from the same donors did not upregulate PD-1 and maintained the production of high levels of cytokines. Blocking PD-1 engagement to its ligand (PD-L1) enhanced the capacity of HIV-specific CD8+ T cells to survive and proliferate and led to an increased production of cytokines and cytotoxic molecules in response to cognate antigen. The accumulation of HIV-specific dysfunctional CD8+ T cells in the infected host could prevent the renewal of a functionally competent HIV-specific CD8+ repertoire.
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Acknowledgements
We thank P. Wilkinson, L. Greller and R. Somogyi for the statistical analyses and M. Lainesse for technical assistance. This work was supported by grants awarded to R.-P.S. from the US National Institutes of Health, the Canadian Institutes of Health Research, the Canadian Network for Vaccine and Immunotherapeutics, Genome Québec, Genome Canada and the Réseau SIDA FRSQ. R.-P.S. is the Canada Research Chair in Human Immunology. J.-P.R. is a scientific scholar receiving support from the Fonds de la Recherche en Santé du Québec (FRSQ). We also thank B. Walker, R. Koup and R. Ahmed for discussions.
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L.T. did the experiments and wrote the paper. L.J., N.C., E.A.S. and S.G. gave previous help with the final experiments and with writing the paper. B.B. generated pMHC monomers. J.-P.R. and R.S.B. provided samples from research subjects. E.D. performed the viral sequencing. H.S. and R.S.B. developed the CBA cytotoxic kit. Co-senior authors E.K.H. and R.-P.S. supervised all experiments and wrote the paper.
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Supplementary information
Supplementary Fig. 1
Longitudinal analysis of PD-1 expression on HIV-specific CD8 T cells correlates with viremia. (PDF 577 kb)
Supplementary Fig. 2
Percentage of cytokine production of tetramer-positive cells is a function of levels of PD-1 expression. (PDF 590 kb)
Supplementary Fig. 3
Increased TNF-α production in HIV-specific CD8 T cells in a 6-d culture stimulation in the presence of anti-PD-L1 antibody. (PDF 733 kb)
Supplementary Table 1
Characteristics of participants with percentages of tetramer positive CD8+ T cells. (PDF 50 kb)
Supplementary Table 2
Phenotypic analysis of CMV-, EBV- and HIV-specific tetramer-positive cells in viremic and aviremic individuals. (PDF 40 kb)
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Trautmann, L., Janbazian, L., Chomont, N. et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12, 1198–1202 (2006). https://doi.org/10.1038/nm1482
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DOI: https://doi.org/10.1038/nm1482
