Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion
Zheng Zhang, Liang Cheng, Juanjuan Zhao, Guangming Li, Liguo Zhang, Weiwei Chen, Weiming Nie, Natalia J. Reszka-Blanco, Fu-Sheng Wang, Lishan Su
Zheng Zhang, Liang Cheng, Juanjuan Zhao, Guangming Li, Liguo Zhang, Weiwei Chen, Weiming Nie, Natalia J. Reszka-Blanco, Fu-Sheng Wang, Lishan Su
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Research Article AIDS/HIV

Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion

Abstract

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.

Authors

Zheng Zhang, Liang Cheng, Juanjuan Zhao, Guangming Li, Liguo Zhang, Weiwei Chen, Weiming Nie, Natalia J. Reszka-Blanco, Fu-Sheng Wang, Lishan Su

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Figure 4

Persistent HIV-1 infection in NRG-hu mice depletes ILC3s and preferentially impairs their activity in IL-17a production.

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Persistent HIV-1 infection in NRG-hu mice depletes ILC3s and preferentia...
NRG-hu mice were treated as described in the Figure 3 legend. (A) Representative FACS plots show the depletion and cART rescue of ILC3s in mLN, spleen, and BM of NRG-hu mice with persistent HIV-1 infection. Numbers indicate percentages of ILC3s within hCD45+Lin– cells. (B) Summary data of the percentages of ILC3s from mLN, spleen, and BM in mock (n = 12), HIV-1–infected (n = 6), and HIV-1–infected with cART-treated NRG-hu mice (n = 8). Overall, for ILC3 percentages, P = 0.0237 (mLN); P = 0.0088 (spleen); P = 0.0178 (BM). For ILC3 cell counts, P = 0.0339 (mLN); P = 0.0024 (spleen); P = 0.0404 (BM), 1-way ANOVA. *P < 0.05; **P < 0.01, Tukey’s post-hoc test. Data are representative of 3 independent experiments with 3 to 4 donors. (C) Representative FACS plots show IL-17a production by splenic ILC3s stimulated with PMA plus ionomycin for 4 hours. Numbers indicate percentages of cytokine-producing ILC3s. (D) Summary data of cytokine-producing ILC3s from spleens of mock-infected (n = 7), HIV-1–infected (n = 5), and HIV-1–infected with cART-treated NRG-hu mice (n = 4). Data are representative of 2 independent experiments with 3 to 4 donors. Overall, for percentages of ILC3s from spleen, P = 0.0051 (IL-17); P = 0.0484 (IL-22); P = 0.0921 (IFN-γ); P = 0.7237 (IL-13), 1-way ANOVA. *P < 0.05; **P < 0.01, Tukey’s post-hoc test.