TY - JOUR
T1 - Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction
AU - Trautmann, Lydie
AU - Janbazian, Loury
AU - Chomont, Nicolas
AU - Said, Elias A.
AU - Gimmig, Sylvain
AU - Bessette, Benoit
AU - Boulassel, Mohamed Rachid
AU - Delwart, Eric
AU - Sepulveda, Homero
AU - Balderas, Robert S.
AU - Routy, Jean Pierre
AU - Haddad, Elias K.
AU - Sekaly, Rafick Pierre
N1 - Funding Information:
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.
PY - 2006/10
Y1 - 2006/10
N2 - 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.
AB - 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.
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U2 - 10.1038/nm1482
DO - 10.1038/nm1482
M3 - Article
C2 - 16917489
AN - SCOPUS:33749009709
SN - 1078-8956
VL - 12
SP - 1198
EP - 1202
JO - Nature Medicine
JF - Nature Medicine
IS - 10
ER -