Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection

Abstract

More than 10% of the world’s population is chronically infected with HIV, HCV or HBV, which cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as Programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate clearance of chronic viral infections. We have identified that the prostaglandin E2 (PGE2) receptors EP2 and EP4 are upregulated on virus-specific CTLs during chronic LCMV infection and suppress CTL survival and function. We showed that the combined blockade of PGE2 and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE2 inhibition is both independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for treatment of HIV and other chronic viral infections.

The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

“…In addition, several genes encoding products known to promote T cell dysfunction, including intracellular metallothioneins ( Mt1 and Mt2 ), which contribute to T cell dysfunction in mouse tumors, as well as the transcription factor c-Maf ( Maf ) and the receptor for prostaglandin E 2 ( Ptger2 ), which contribute to CD8 + T cell dysfunction in a model of chronic infection with lymphocytic choriomeningitis virus (LCMV) clone 13 (refs. 1,24,25), had higher expression in wild-type CD8 + T cells than in Mir31 −/− CD8 + T cells (Fig. 4a,b).…”

“…In vitro studies have shown that prostaglandin E 2 inhibits the function of cytotoxic T lymphocytes and strongly suppresses the production of cytokines. Inhibition of the production of prostaglandin E 2 with an inhibitor of the cyclooxygenase COX-2 has demonstrated synergy with blockade of PD-1 and improved T cell function 24 . Our data showed that expression of miR-31 was able to increase expression of the receptor for prostaglandin E 2 in CD8 + T cells following stimulation with type I interferons.…”

Leishmania donovani-Induced Prostaglandin E2 Generation Is Critically Dependent on Host Toll-Like Receptor 2–Cytosolic Phospholipase A2 Signaling

“…A growing body of evidence highlights the importance of this lipid mediator in the immunopathology of cancer (5-7) and infectious diseases caused by protozoa, viruses, and bacteria (4,(32)(33)(34)(35). Several species of Leishmania are reported to upregulate macrophage PGE2 production and to exploit the immunosuppressive properties of PGE2 to survive within the hostile intramacrophagic environment (13,36,37).…”

Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulate the level of PD‑1 in infiltrating CD8+ T cells in patients with lung cancer

“…The activation of PD-1/PD-L1 signaling in tumors can inhibit T cell function and weaken the immune response, leading to a poor prognosis (10)(11)(12). Blocking a combination of PGE2 and PD-1 signaling has been reported to be therapeutic in chronic lymphocytic choriomeningitis virus infection by augmenting the numbers of functional virus-specific cytotoxic T lymphocytes via PGE2 receptors, EP2 and EP4 (9,13). However, whether a direct association exists between PGE2 and PD-1 remains unclear.…”