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

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. 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.

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.…”

“…40 Viral quantification. Quantification of plasma SIV RNA levels was assessed by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), 40 and viral replication in tissues was assessed by in situ hybridization using a 35 S-labeled RNA probe derived from pBluescript encoding the SIVmac nef gene, as previously described. 40 Immunohistochemical analyses.…”

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.…”

A brief history of CD8 T cells

“…Finally, work throughout this time revealed the dramatic detrimental effects of chronic infections on T cell function and memory T cell differentiation including T cell exhaustion and deletion and improper memory T cell development [69]. These studies have led to promising new therapeutic approaches that may restore immunity during persisting infections [70][71][72][73][74]. Our understanding of immunological memory, memory T cell differentiation and the mechanisms that control T cell (and perhaps B cell) dysfunction during chronic infections, however, remains incomplete.…”