title: Expansion of myeloid-derived suppressor cells promotes differentiation of regulatory T cells in HIV-1+ individuals.
abstract: 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.
  
  
  
  In this study, we provide evidence that HIV-induced expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) promote the differentiation of Foxp3 Tregs.
  
  
  
  We measured MDSC induction and cytokine expression by flow cytometry and analyzed their functions by coculturing experiments.
  
  
  
  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.
  
  
  
  These results suggest that HIV-induced MDSCs promote Treg cell development and inhibit T cell function - a hallmark of many chronic infectious diseases.
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: Jun P
authors.initials: JP
authors.lastname: Ren
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: Xiao Y
authors.initials: XY
authors.lastname: Wu
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: Zheng D
authors.initials: ZD
authors.lastname: Morrison
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Elgazzar
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.
authors.forename: Shun B
authors.initials: SB
authors.lastname: Ning
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.|HIV/HCV Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, Tennessee 37614.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Moorman
authors.affiliation: Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.|Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614.|HIV/HCV Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, Tennessee 37614.
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000032:analysis; D015658:HIV Infections / Q000473:pathology*; D006801:Humans; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000502:physiology*
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors