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

L Trautmann, L Janbazian, N Chomont, EA Said… - Nature medicine, 2006 - nature.com
L Trautmann, L Janbazian, N Chomont, EA Said, S Gimmig, B Bessette, MR Boulassel
Nature medicine, 2006nature.com
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.,,). 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 …
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. ,,). 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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