PD-1, IL-10 and IFN-γ form a network to regulate HIV-specific CD4 T cell dysfunction (105.2)

Abstract

Abstract Blockade of the PD-1 or IL-10 pathways can restore antigen-specific T cell functions in chronic infections and cancer. PD-1 blockade is currently evaluated in oncology trials and is also considered in HIV infection. It is thus crucial to define the immune restoration elicited by these interventions, and to determine whether combined blockade of these molecules can synergistically revive immune function. We investigated 40 subjects at different stages of HIV infection. We measured proliferation and cytokine production by HIV-specific CD4 T cells stimulated with HIV Gag in the presence of blocking antibodies against PD-L1 and/or IL-10Rα, or IFN-γ. We also determined the modulatory impact of IFN-γ on PD-1 and its ligands on different cell subsets. In viremic subjects, combined blockade of PD-L1 and IL-10Rα resulted in a striking synergistic increase in IFN-γ secretion by HIV-specific CD4 T cells in contrast to only a moderate increase in IL-2 and IL-13 secretion, and proliferation. While IL-10Rα blockade preferentially increased IFN-γ, PD-L1 blockade had a balanced effect on IFN-γ, IL-2 and IL-13. Stimulation of HIV-specific CD4 T cells led to strong up-regulation of PD-L1 on monocytes that was further increased by anti-IL-10Rα. Blockade of IFN-γ abrogated PD-L1 induction and restored proliferation of HIV-specific CD4 T cells. These data provide a mechanistic insight on how the interplay between PD-1, IL-10 and IFN-γ regulates Thelper dysfunction in HIV infection.