HIV Type 1 gp120-Induced Expansion of Myeloid Derived Suppressor Cells Is Dependent on Interleukin 6 and Suppresses Immunity
HIV Type 1 gp120-Induced Expansion of Myeloid Derived Suppressor Cells Is Dependent on Interleukin 6 and Suppresses Immunity
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DOI：
10.1093/infdis/jit469
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发表时间：
2014-02-01
影响因子：
6.4
通讯作者：
Spector, Stephen A.
中科院分区：
文献类型：
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作者：
Garg, Ankita;Spector, Stephen A.
背景在人类免疫缺陷病毒1型（HIV）感染期间，髓源性抑制细胞（MDSC）扩增和T细胞功能障碍的相关因素尚不清楚。本研究探讨MDSCs在HIV感染过程中的作用。将外周血单核细胞（PBMC）与gp 120和感染性或灭活的HIV（有或没有抗白细胞介素6（IL-6）抗体）一起培养。从PBMC中分离出CD 33（+）、CD 4（+）和CD 8（+）细胞，并在存在或不存在诱导型一氧化氮合酶（iNOS）、活性氧（ROS）和抗氧化酶1抑制剂的情况下进行共培养。通过流式细胞术评估CD 11b（+）CD 33（+）CD 14（+）HLA-DR-/lo MDSC、磷酸化STAT 3（pSTAT 3）和CD 4（+）CD 25（+）FoxP 3（+）细胞。采用酶联免疫吸附试验定量测定IL-6、干扰素γ（IFN-γ）、白细胞介素10（IL-10）和gp 120水平。当PBMC暴露于感染性或灭活的HIV时，MDSC扩增。暴露于gp 120导致MDSC扩增，IL-6水平和pSTAT 3表达增加。抗IL-6消除MDSC扩增和pSTAT 3表达。gp 120-扩增的CD 33（+）MDSC抑制IFN-γ从自体T细胞的释放，其在ROS和iNOS抑制后恢复。在CD 4（+）T细胞共培养物中，gp 120扩增的CD 33（+）MDSC增加IL-10和CD 4（+）CD 25（+）FoxP 3（+）调节性T细胞水平。最后，与健康对照组相比，HIV感染者中MDSC的频率较高。这些发现表明，HIV gp 120诱导IL-6和MDSC扩增，这有助于通过调节细胞因子和细胞反应来抑制免疫。
Background. Factors responsible for myeloid-derived suppressor cell (MDSC) expansion and T-cell dysfunction during human immunodeficiency virus type 1 (HIV) infection are unknown. This study investigated the role of MDSCs during HIV infection.Methods. Peripheral blood mononuclear cells (PBMCs) were cultured with gp120 and infectious or inactivated HIV, with or without anti-interleukin 6 (IL-6) antibody. CD33(+), CD4(+), and CD8(+) cells were isolated from PBMCs and cocultured in the presence or absence of inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), and arginase 1 inhibitors. CD11b(+)CD33(+)CD14(+)HLA-DR-/lo MDSCs, phosphorylated STAT3 (pSTAT3), and CD4(+)CD25(+)FoxP3(+) cells were evaluated by flow cytometry. IL-6, interferon gamma (IFN-gamma), interleukin 10 (IL-10), and gp120 levels were quantified by an enzyme-linked immunosorbent assay.Results. MDSCs expanded when PBMCs were exposed to infectious or inactivated HIV. Exposure to gp120 led to MDSC expansion, with increases in IL-6 levels and pSTAT3 expression. Anti-IL-6 abrogated MDSC expansion and pSTAT3 expression. gp120-expanded CD33(+) MDSCs inhibited IFN-gamma release from autologous T cells, which was restored upon ROS and iNOS inhibition. gp120-expanded CD33(+) MDSCs increased IL-10 and CD4(+)CD25(+)FoxP3(+) regulatory T-cell levels in CD4(+) T-cell cocultures. Finally, high frequencies of MDSCs were present in HIV-infected persons, compared with healthy controls.Conclusions. These findings demonstrate that HIV gp120 induces IL-6 and MDSC expansion, which contributes to immune suppression by modulating cytokine and cellular responses.