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 7

HIV-1 infection upregulates CD95 on ILC3s through pDC/IFN-I–dependent mechanisms.

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HIV-1 infection upregulates CD95 on ILC3s through pDC/IFN-I–dependent me...
(A and B) Representative histograms (A) and summary data (B) indicate percentages of CD95-expressing ILC3s in spleens from mock (n = 4) and HIV-1–infected (n = 6) NRG-hu mice and HC (n = 10) and HIV-1–infected patients (n = 12). **P < 0.01; ***P < 0.001 (unpaired t test). Data are representative of 2 independent experiments with humanized mice from 2 to 3 donor tissues. (C) Representative histograms show percentages of CD95-expressing ILC3s incubated ex vivo for 72 hours alone (gray), with IFN-α (blue line), with HIV-1 alone (red line), or with HIV-1 plus pDC immunotoxin 15B-sap (black line) or anti–IFN-α/β receptor Abs (shade). Data are representative of 3 independent experiments with 2 donors. (D) HIV-1 infection increases the sensitivity of ILC3s to CD95/FasL-induced apoptosis via pDC-produced IFN-I. Spleen cells from NRG-hu mice were preincubated with mock, HIV-1 alone, or HIV-1 in the presence of anti–IFN-α/β receptor Abs (10 μg/ml) for 72 hours and then stimulated with plate-coated anti-Fas Abs (5 μg/ml) for 12 hours. *P < 0.05; **P < 0.01, ANOVA with Tukey’s post-hoc test. (E) IFN-I increases the sensitivity of T cells to CD95/Fas-induced death in HIV-1–infected individuals. PBMCs from HC (n = 5) and HIV-1–infected subjects (n = 5) were stimulated with plate-bound anti-Fas Ab for 6 hours. Cells were then harvested and stained for active caspase-3. **P < 0.01; ***P < 0.001, unpaired t test. (F–H) Representative histograms (F) and summary data show percentages of active caspase-3–expressing splenic ILC3s (G) and live ILC3 cell counts (H) relative to mock. Spleen cells from NRG-hu mice were incubated 72 hours ex vivo alone (mock) or with HIV-1 in the presence of no Ab (medium), isotype control Ab (IgG), anti-FasL Ab (10 μg/ml), or Zvad (50 μM). The percentage of ILC3s expressing active caspase-3 was measured.*P < 0.05; **P < 0.01, compared with mock; #P < 0.05, compared with HIV+IgG (Tukey’s post-hoc test). Data are representative of 2 independent experiments with 2 donors. (I) A model of HIV-1–induced ILC3 depletion. Activation of pDCs by HIV-1 infection expresses IFN-I, which upregulates CD95 expression and sensitizes tissue-resident ILC3s to CD95/FasL-mediated apoptosis.