Wang Ling, Zhao Juan, Ren Jun P, Wu Xiao Y, Morrison Zheng D, Elgazzar Mohamed A, Ning Shun B, Moorman Jonathan P, Yao Zhi Q
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.
AIDS. 2016 Jun 19;30(10):1521-1531. doi: 10.1097/QAD.0000000000001083.
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.
调节性T细胞（Tregs）通过损害抗病毒免疫促进HIV-1疾病进展；然而，在HIV-1感染情况下Tregs发育的确切机制尚不完全清楚。
在本研究中，我们提供证据表明HIV诱导的单核细胞来源的髓系抑制细胞（M-MDSCs）扩增促进Foxp3 Tregs的分化。
我们通过流式细胞术测量MDSC诱导和细胞因子表达，并通过共培养实验分析其功能。
与健康参与者相比，我们观察到HIV-1血清阳性（HIV-1）个体外周血中M-MDSC频率显著增加，即使是那些接受抗逆转录病毒治疗且病毒血症无法检测到的个体。我们还观察到，在体外将健康外周血单个核细胞（PBMCs）与HIV-1蛋白（gp120或Tat）或Toll样受体4配体脂多糖孵育后，M-MDSCs增加，在存在磷酸化信号转导和转录激活因子3抑制剂STA-21的情况下，这种效应可以被消除。功能分析表明，来自HIV-1个体的M-MDSCs表达更高水平的IL-10、肿瘤生长因子-β、IL-4受体α、p47、程序性死亡配体1和磷酸化信号转导和转录激活因子3，所有这些都是已知的骨髓生成和免疫抑制介质。重要的是，将健康CD4 T细胞与来自HIV-1个体的MDSCs孵育显著增加了Foxp3 Tregs的分化。此外，从HIV-1个体的PBMCs中耗尽MDSCs导致Foxp3 Tregs显著减少，CD4 T效应细胞产生的IFNγ增加。
这些结果表明，HIV诱导的MDSCs促进Treg细胞发育并抑制T细胞功能，这是许多慢性传染病的一个标志。
