Polymorphonuclear myeloid-derived suppressor cells regulates immune recovery during HIV infection through PD-L1 and TGF-β pathways

Although MDSCs are widely recognized for their immunoinhibitory effects in pathological conditions, their function during HIV infection particularly within the mechanisms underlying incomplete immune recovery remains elusive. We conducted a cross-sectional study in which 30 healthy controls and 62 HIV-1-infected subjects [31 immunological non-responders (INRs) and 31 immunological responders (IRs)] were selected. The proportion of MDSCs was determined in each category of participants. Using flow cytometry and real-time PCR, immune regulatory molecules (including PD-L1, ARG1, iNOS, IL-10, TGF-β, and IDO) that are relevant for MDSCs activity were quantified. Furthermore, we investigated the impact of the blockade of PD-L1 and TGF-β pathways on MDSCs and their effects on CD4+ T-cells using functional experiments. PMN-MDSCs are more abundant and are negatively correlated to CD4 counts in HIV-infected individuals. In addition, PMN-MDSCs suppress CD4+ T-cell proliferation and IFN-γ production in INRs. Furthermore, correlations were found between PD-L1 expression on PMN-MDSCs and PD-1+ CD4+ T-cells. TGF-β expression on PMN-MDSCs was likewise enhanced in INRs. Importantly, inhibiting both PD-L1 and TGF-β pathways had a synergistic impact on restoring CD4+ T-cell activity . PMN-MDSCs expansion inhibits CD4+ T-cell responses. We suggest that targeting PD-L1 and TGF-β pathways together may significantly improve immune recovery in INRs.