Nature Medicine
- 12, 1198 - 1202 (2006)
Published online: 20 August 2006; | doi:10.1038/nm1482
There is a Corrigendum (November 2006) associated with this Letter.
Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunctionLydie Trautmann1, 2, 3, Loury Janbazian1, 4, 8, Nicolas Chomont1, 2, 3, 8, Elias A Said1, 2, 3, Sylvain Gimmig1, Benoit Bessette1, Mohamed-Rachid Boulassel5, Eric Delwart6, Homero Sepulveda7, Robert S Balderas7, Jean-Pierre Routy3, 5, Elias K Haddad1, 2, 3, 4 & Rafick-Pierre Sekaly1, 2, 3, 41
Laboratoire d'Immunologie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM) Saint-Luc, 264 Rene Levesque Est, Montréal, Québec H2X1P1, Canada. 2
Laboratoire d'Immunologie, Département de Microbiologie et d'Immunologie, Université de Montréal, Québec, Canada. 3
INSERM U743, CR-CHUM, Université de Montréal, 264 Rene Levesque Est, Montréal, Québec H2X1P1, Canada. 4
Department of Microbiology and Immunology, 3775 University Street, McGill University, Montréal, Québec H3A 2B4, Canada. 5
Immunodeficiency Service and Division of Haematology, Royal Victoria Hospital, McGill University Health Centre, McGill University, 687 Pine Avenue West, Montréal, Québec H3A 1A1, Canada. 6
Blood Systems Research Institute, 270 Masonic Avenue, San Francisco, California 94118, USA. 7
BD Biosciences, 10975 Torreyana Road, San Diego, California 92121, USA. 8
These authors contributed equally to this work.
Correspondence should be addressed to Rafick-Pierre Sekaly rafick-pierre.sekaly@umontreal.ca 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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