Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction.
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.
Trautmann
Lydie
L
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.
Janbazian
Loury
L
Chomont
Nicolas
N
Said
Elias A
EA
Gimmig
Sylvain
S
Bessette
Benoit
B
Boulassel
Mohamed-Rachid
MR
Delwart
Eric
E
Sepulveda
Homero
H
Balderas
Robert S
RS
Routy
Jean-Pierre
JP
Haddad
Elias K
EK
Sekaly
Rafick-Pierre
RP
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000096:biosynthesis*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D017252:CD3 Complex / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D015658:HIV Infections / Q000097:blood* / Q000378:metabolism*; D006801:Humans; D007107:Immune System / Q000473:pathology*; D007154:Immune System Diseases / Q000276:immunology* / Q000473:pathology; D016130:Immunophenotyping; D008969:Molecular Sequence Data; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015854:Up-Regulation
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D017252:CD3 Complex; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell