Plasmacytoid dendritic cells promote HIV-1-induced group 3 innate lymphoid cell depletion.
Plasmacytoid dendritic cells promote HIV-1-induced group 3 innate lymphoid cell depletion.
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DOI：
10.1172/jci82124
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
Zheng Zhang;L. Cheng;Juanjuan Zhao;Guangming Li;Liguo Zhang;Weiwei Chen;Weimin Nie;Natalia J. Reszka-Blanco;Fu-Sheng Wang;L. Su
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文献类型：
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作者：
Zheng Zhang;L. Cheng;Juanjuan Zhao;Guangming Li;Liguo Zhang;Weiwei Chen;Weimin Nie;Natalia J. Reszka-Blanco;Fu-Sheng Wang;L. Su
第3组先天淋巴样细胞（ILC 3）已被证明在促进抗菌免疫，维持上皮屏障功能和支持组织修复中发挥作用。ILC 3改变与慢性炎症和炎性疾病相关;然而，由于缺乏稳健的模型，该细胞群在HIV-1感染中的特征和相关调控机制知之甚少。在这里，我们确定了功能性人ILC 3在人源化小鼠的淋巴器官中发育，并且在该模型中持续的HIV-1感染会耗尽ILC 3，正如在慢性HIV-1感染患者中观察到的那样。在HIV-1感染的小鼠中，有效的抗逆转录病毒治疗逆转了ILC 3的丢失。ILC 3的HIV-1依赖性减少需要浆细胞样树突状细胞（pDC）、IFN-I和CD 95/FasL途径，因为靶向消耗或阻断这些分别在体内和体外防止HIV-1诱导的ILC 3消耗。最后，我们确定HIV-1感染通过pDC和IFN-I依赖性机制诱导ILC 3上的CD 95表达，该机制使ILC 3敏感，从而经历CD 95/FasL介导的凋亡。我们的结论是，慢性HIV-1感染耗尽ILC 3通过pDC激活，诱导IFN-Ⅰ，和CD 95介导的细胞凋亡。
Group 3 innate lymphoid cells (ILC3s) have demonstrated roles in promoting antibacterial immunity, maintaining epithelial barrier function, and supporting tissue repair. ILC3 alterations are associated with chronic inflammation and inflammatory disease; however, the characteristics and relevant regulatory mechanisms of this cell population in HIV-1 infection are poorly understood due in part to a lack of a robust model. Here, we determined that functional human ILC3s develop in lymphoid organs of humanized mice and that persistent HIV-1 infection in this model depletes ILC3s, as observed in chronic HIV-1-infected patients. In HIV-1-infected mice, effective antiretroviral therapy reversed the loss of ILC3s. HIV-1-dependent reduction of ILC3s required plasmacytoid dendritic cells (pDCs), IFN-I, and the CD95/FasL pathway, as targeted depletion or blockade of these prevented HIV-1-induced ILC3 depletion in vivo and in vitro, respectively. Finally, we determined that HIV-1 infection induces CD95 expression on ILC3s via a pDC- and IFN-I-dependent mechanism that sensitizes ILC3s to undergo CD95/FasL-mediated apoptosis. We conclude that chronic HIV-1 infection depletes ILC3s through pDC activation, induction of IFN-I, and CD95-mediated apoptosis.