Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion
Zheng Zhang, … , Fu-Sheng Wang, Lishan Su
Zheng Zhang, … , Fu-Sheng Wang, Lishan Su
Published August 24, 2015
Citation Information: J Clin Invest. 2015;125(9):3692-3703. https://doi.org/10.1172/JCI82124.
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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 6

HIV-1 infection leads to ILC3 depletion via pDC- and IFN-I–dependent mechanisms.

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HIV-1 infection leads to ILC3 depletion via pDC- and IFN-I–dependent mec...
(A and B) Representative FACS plots (A) and summary data (B) show splenic ILC3 percentages within CD45+Lin– cells in mock (n = 9), HIV-1–infected (n = 7), and HIV-1–infected/pDC-depleted (n = 9) NRG-hu mice. Data are representative of 3 independent experiments with 3 donors. Overall, for ILC3 percentages, P < 0.0001, 1-way ANOVA.*P < 0.05; **P < 0.01, Tukey’s post-hoc test. (C and D) Summary data of IL-17a–producing (C) and IL-22–producing (D) ILC3s from spleens of mock (n = 4), HIV-1 (n = 4), and HIV-1+15B (n = 5) mice. Data are representative of 2 independent experiments with 2 donors. Overall, for ILC3 percentages, P = 0.0039 (IL-17a); P = 0.0031 (IL-22), 1-way ANOVA. *P < 0.05; **P < 0.01, Tukey’s post-hoc test. (E and F) Representative histograms (E) and summary data (F) show the percentages of active caspase-3–expressing splenic ILC3s within hCD45+Lin– cells in mock (n = 4), HIV-1–infected (n = 4), and HIV-1–infected/pDC depletion (n = 5) NRG-hu mice. Overall, P = 0.0374, 1-way ANOVA; *P < 0.05, Tukey’s post-hoc test. Data are representative of 3 independent experiments with 1 to 3 donors. (G–I) Representative histograms (G) and summary data show the percentages of active caspase-3–expressing ILC3 (H) and total live ILC3 cell counts (I) relative to mock. Spleen cells from NRG-hu mice were incubated for 72 hours ex vivo alone (mock) or infected with HIV-1 in the presence of no Ab (medium), IgG, 15B-sap immunotoxin (8 ng/ml), or anti–IFN-α/β receptor (10 μg/ml) Abs. The percentage of ILC3s expressing active caspase-3 was measured. Data are representative of 2 independent experiments with 2 donors. *P < 0.05; **P < 0.01, compared with mock. #P < 0.05, compared with HIV+IgG (Tukey’s post-hoc test).