Expansion of myeloid-derived suppressor cells promotes differentiation of regulatory T cells in HIV-1+ individuals

AIDS. 2016 Jun 19;30(10):1521-1531. doi: 10.1097/QAD.0000000000001083.


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, p47, 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Differentiation*
  • Cells, Cultured
  • Coculture Techniques
  • Cytokines / biosynthesis
  • Flow Cytometry
  • Forkhead Transcription Factors / analysis
  • HIV Infections / pathology*
  • Humans
  • Myeloid-Derived Suppressor Cells / physiology*
  • T-Lymphocytes, Regulatory / chemistry
  • T-Lymphocytes, Regulatory / physiology*


  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors