Expansion of Myeloid-Derived Suppressor Cells Promotes Differentiation of Regulatory T Cells in HIV-1+ Individuals

• Main Authors: Wang, Ling, Zhao, Juan, Ren, Junping P., Wu, Xiao Y., Morrison, Zheng D., El Gazzar, Mohamed A., Ning, Shunbin, Moorman, Jonathan P., Yao, Zhi Q.
• Format: Others
• Published: Digital Commons @ East Tennessee State University 2016
• Subjects: gp120; HIV-1; myeloid-derived suppressor cells; phosphorylated signal transducer and activator of transcription-3; regulatory T cells; Internal Medicine
• Online Access: https://dc.etsu.edu/etsu-works/6532; https://dc.etsu.edu/cgi/viewcontent.cgi?article=7783&context=etsu-works

Objective: Regulatory T cells (Tregs) contribute to HIV-1 disease progression by impairing antiviral immunity; however, the precise mechanisms responsible for the development of Tregs in the setting of HIV-1 infection are incompletely understood. Design: In this study, we provide evidence that HIV-induced expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) promote the differentiation of Foxp3+ Tregs. Methods: We measured MDSC induction and cytokine expression by flow cytometry and analyzed their functions by coculturing experiments. Results: We observed a dramatic increase in M-MDSC frequencies in the peripheral blood of HIV-1 seropositive (HIV-1+) individuals, even in those on antiretroviral therapy with undetectable viremia, when compared with healthy participants. We also observed increases in M-MDSCs after incubating healthy peripheral mononuclear cells (PBMCs) with HIV-1 proteins (gp120 or Tat) or Toll-like receptor 4 ligand lipopolysaccharides in vitro, an effect that could be abrogated in the presence of the phosphorylated signal transducer and activator of transcription 3 inhibitor, STA-21. Functional analyses indicated that M-MDSCs from HIV-1+ individuals express higher levels of IL-10, tumor growth factor-β, IL-4 receptor α, p47phex, programmed death-ligand 1, and phosphorylated signal transducer and activator of transcription 3 – all of which are known mediators of myelopoiesis and immunosuppression. Importantly, incubation of healthy CD4+ T cells with MDSCs derived from HIV-1+ individuals significantly increased differentiation of Foxp3+ Tregs. In addition, depletion of MDSCs from PBMCs of HIV-1+ individuals led to a significant reduction of Foxp3+ Tregs and increase of IFNγ production by CD4+ T effector cells. Conclusions: These results suggest that HIV-induced MDSCs promote Treg cell development and inhibit T cell function – a hallmark of many chronic infectious diseases.