PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection

Abstract

Here, we report on the expression of programmed death (PD)-1 on human virus-specific CD8+ T cells and the effect of manipulating signaling through PD-1 on the survival, proliferation, and cytokine function of these cells. PD-1 expression was found to be low on naive CD8+ T cells and increased on memory CD8+ T cells according to antigen specificity. Memory CD8+ T cells specific for poorly controlled chronic persistent virus (HIV) more frequently expressed PD-1 than memory CD8+ T cells specific for well-controlled persistent virus (cytomegalovirus) or acute (vaccinia) viruses. PD-1 expression was independent of maturational markers on memory CD8+ T cells and was not directly associated with an inability to produce cytokines. Importantly, the level of PD-1 surface expression was the primary determinant of apoptosis sensitivity of virus-specific CD8+ T cells. Manipulation of PD-1 led to changes in the ability of the cells to survive and expand, which, over several days, affected the number of cells expressing cytokines. Therefore, PD-1 is a major regulator of apoptosis that can impact the frequency of antiviral T cells in chronic infections such as HIV, and could be manipulated to improve HIV-specific CD8+ T cell numbers, but possibly not all functions in vivo.

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

“…Several groups have recently reported that PD-1 expression on peripheral blood CD8 þ T cells is increased during HIV infection and regulate T-cell survival. [34][35][36] Herein, we also demonstrated that induction of PD-1 is increased in Mes LNs of non-controllers and expression of PD-1 is enhanced in vitro by TGF-b. Although, we speculate a role of PD-1 in Mes LNs favoring immunosupression, a formal proof that blockade of PD-1/PD-L1 interaction will restore T-cell function and prevent death remains to be addressed once adequate reagents are available.…”

“…In HIV-infected individuals, it has been shown that blocking such interaction increases the capacity of peripheral blood HIV-specific CD8 þ T cells to proliferate and survive. [34][35][36] While TGF-b appears necessary to prime cells of SIV-infected macaques to undergo apoptosis, it is not sufficient in and by itself to fully induce the process, as we have been unable to induce death by simply adding TGF-b on T cells from healthy macaques, in spite of inducing PD-1 expression. This may however reflect the lack of PD-L1 expression in our in vitro culture system.…”

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

“…5 Increasing evidence demonstrates that upregulation of the PD-1 inhibitory receptor mediates HIV-specific CD8 1 T-cell functional exhaustion and CD8 1 T cell is apoptosis-sensitive, resulting in an impairment of CD8 1 T cell's ability to control virus replication. [6][7][8][9] Involvement of the PD-1 pathway has also been shown during hepatitis B and C virus infection [10][11][12][13] with PD-L1 expression demonstrated in situ on a wide variety of solid tumors including pancreas, lung, ovarian and bladder tumors. [14][15][16][17][18] Studies relating PD-L1 expression on tumors to disease outcome show that PD-L1 expression strongly correlates with unfavorable prognosis in kidney, bladder, gastric and pancreatic cancer.…”

Sanctuaire du virus de l’immunodéficience humaine et mécanismes d’échappement

“…Cette observation est d'autant plus intéressante que cette enzyme, qui catabolisme le tryptophane et influence la capacité de prolifération des cellules, joue également un rôle sur la survie cellulaire [29]. De récents travaux ont décrit l'expression de la molécule PD-1 (programmed death molecule 1) par les lymphocytes T CD8 de patients infectés par le VIH-1 et de macaques infectés par le VIS [30][31][32][33][34]43]. Nos propres travaux indiquent une augmentation de l'expression de PD-1 dans les lymphocytes T CD8 isolés à partir des ganglions mésen-tériques.…”