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

Lydie Trautmann, Loury Janbazian, Nicolas Chomont, Elias A. Said, Sylvain Gimmig, Benoit Bessette, Mohamed Rachid Boulassel, Eric Delwart, Homero Sepulveda, Robert S. Balderas, Jean Pierre Routy, Elias K. Haddad, Rafick Pierre Sekaly

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1033 Citations (Scopus)

Abstract

The engagement of programmed death 1 (PD-1) to its ligands, PD-L1 and PD-L2, 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 load. During chronic HIV infection, HIV-specific CD8+ T cells are functionally impaired, showing a reduced capacity to produce cytokines and effector molecules as well as an impaired capacity to proliferate. 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.

Original languageEnglish
Pages (from-to)1198-1202
Number of pages5
JournalNature Medicine
Volume12
Issue number10
DOIs
Publication statusPublished - Oct 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Trautmann, L., Janbazian, L., Chomont, N., Said, E. A., Gimmig, S., Bessette, B., Boulassel, M. R., Delwart, E., Sepulveda, H., Balderas, R. S., Routy, J. P., Haddad, E. K., & Sekaly, R. P. (2006). Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nature Medicine, 12(10), 1198-1202. https://doi.org/10.1038/nm1482