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

Abstract

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 co-culturing 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 (ART) with undetectable viremia, when compared to healthy subjects. 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 (TLR) 4 ligand Lipopolysaccharides (LPS) in vitro, an effect that could be abrogated in the presence of the pSTAT-3 inhibitor, STA-21. Functional analyses indicated that M-MDSCs from HIV-1+ individuals express higher levels of IL-10, TGF-β, IL-4Rα, p47phex, PD-L1, and pSTAT-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 IFN-γ production by CD4+ T effector cells (Teffs). Conclusions These results suggest that HIV-induced MDSCs promote Treg cell development and inhibit T cell function - a hallmark of many chronic infectious diseases.

Decline of miR‐124 in myeloid cells promotes regulatory T‐cell development in hepatitis C virus infection

“…We and others have recently shown marked expansion of MDSCs, which suppress T‐cell responses, in patients with chronic viral infections; however, the underlying mechanisms for their suppressive activities remain incompletely understood. The differentiation and maturation of the myeloid lineage (myelopoiesis) are orchestrated by interdependent interactions between cytokine receptors, transcription factors, and as recently described, miRNAs .…”

Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade

“…As MDSC have been shown to promote the differentiation of Tregs, it is possible that the reduction of Tregs is secondary to the blunting of the immunosuppressive activity of MDSC by DC101. 61,62 Alternatively, decreased angiogenesis may hamper Tregs recruitment to the tumor and metastatic sites. DC101 treatment did not cause a significant mobilization and accumulation of MDSC but played a role on their suppressive function.…”

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

“…Retroviral infection also induces MDSCs. In vitro derived MDSCs, via stimulation of PBMCs with the HIV glycoprotein 120 (gp120), or ex vivo MDSCs derived from HIVinfected patient blood inhibited polyclonal and Ag-specific CD4 + and CD8 + T cell proliferation and IFN-c production (8,50,122,155) and increased FoxP3 + CD4 + Treg differentiation (159). In these studies, inhibitory activity was independent of the phenotype of the MDSCs, which were either monocytic like (8,50,122) or granulocytic like (155).…”