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Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction

A Corrigendum to this article was published on 01 November 2006

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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Figure 1: PD-1 is upregulated on HIV-specific CD8+ T cells.
Figure 2: Longitudinal analysis: PD-1 expression on HIV-specific CD8+ T cells correlates with viremia.
Figure 3: Pre-terminally differentiated phenotype and functional impairment of PD-1hi HIV-specific CD8+ T cells.
Figure 4: Blocking the PD-1–PD-L1 pathway increases effector molecules production and proliferation of HIV-specific CD8+ T cells.

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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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Authors and Affiliations

Authors

Contributions

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.

Note: Supplementary information is available on the Nature Medicine website.

Corresponding author

Correspondence to Rafick-Pierre Sekaly.

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The authors declare no competing financial interests.

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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