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T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation

Nature Immunology volume 18, pages 1117–1127 (2017)Cite this article

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An Author Correction to this article was published on 29 June 2018

Abstract

The transcription factor T-bet has been associated with increased susceptibility to systemic and organ-specific autoimmunity, but the mechanism by which T-bet expression promotes neuroinflammation remains unknown. In this study, we demonstrate a cardinal role of T-bet-dependent NKp46+ innate lymphoid cells (ILCs) in the initiation of CD4+ TH17-mediated neuroinflammation. Loss of T-bet specifically in NKp46+ ILCs profoundly impaired the ability of myelin-reactive TH17 cells to invade central nervous system (CNS) tissue and protected the mice from autoimmunity. T-bet-dependent NKp46+ ILCs localized in the meninges and acted as chief coordinators of meningeal inflammation by inducing the expression of proinflammatory cytokines, chemokines and matrix metalloproteinases, which together facilitated T cell entry into CNS parenchyma. Our findings uncover a detrimental role of T-bet-dependent NKp46+ ILCs in the development of CNS autoimmune disease.

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Figure 1: T-bet expression in T cells is insufficient to cause EAE.
Figure 2: Peripheral licensing of CD4+ TH17 cells in Tbx21−/− host.
Figure 3: T-bet-expressing cells in the CNS during EAE.
Figure 4: T-bet-dependent NKp46+ ILCs initiate TH17-mediated EAE.
Figure 5: Localization of T-bet-dependent NKp46+ ILCs during EAE.
Figure 6: Pathogenic function of T-bet maps to ILC1/NKp46+ ILC3.
Figure 7: NKp46+ ILCs regulate infiltration of CD4+ TH17 cells.
Figure 8: NKp46+ ILCs regulate the stability of CD4+ TH17 cells.

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Acknowledgements

We thank Y. Belkaid and A. Singer for critical review of the manuscript; S. Sharrow, L. Granger and A. Adams for flow cytometry and cell sorting; T. Loo for technical assistance; and the members of the laboratories of A. Singer and H. Park for discussions. S. Reiner (Columbia University) generously provided the Tbx21f/f mice. This study was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research (ZIA BC 011431 and ZIA BC 011432 to V.L.) and National Institute of Neurological Disorders and Stroke (1ZIA NS 003111-08 and 1ZIA NS 003112-08 to D.B.M.).

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Author notes

  1. Brandon Kwong and Rejane Rua: These authors contributed equally to this work.

Authors and Affiliations

  1. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Brandon Kwong, Yuanyuan Gao, John Flickinger Jr, Yan Wang, Michael J Kruhlak & Vanja Lazarevic

  2. Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA

    Rejane Rua & Dorian B McGavern

  3. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Jinfang Zhu

  4. Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France

    Eric Vivier

  5. AP–HM Hôpital de la Timone, Serce d'Immunologie, Marseille, France

    Eric Vivier

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Contributions

B.K. conducted the experiments, analyzed the data and contributed to the first draft of the manuscript. R.R., Y.G., J.F. and Y.W. conducted experiments and analyzed data. D.B.M. contributed to experimental design and manuscript preparation. M.J.K. performed quantification of apoptotic cells in the CNS in a blinded manner. E.V. and J.Z. generated NKp46-Cre+ and T-bet ZsGreen reporter mice, respectively. V.L. designed and directed the study, conducted the experiments, analyzed the data and wrote the manuscript.

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Correspondence to Vanja Lazarevic.

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E.V. is the cofounder of and a shareholder in Innate Pharma.

Integrated supplementary information

Supplementary Figure 1 T-bet expression in endogenous (host-derived) T cells is not required for EAE induction by 2D2 WT TH17 cells.

(a) Flow cytometric analysis of CNS-infiltrating CD4+ T cells following adoptive transfer of 7.5 × 106 2D2 WT TH17 cells into Tbx21f/f or Tbx21f/f CD4-Cre+ recipient mice. CNS-infiltrating cells were harvested at the peak of EAE disease (day 16 post-transfer) and analyzed for the fraction of 2D2 (Vβ11+) versus endogenous (Vβ11−) cells among live CD4+ T cells. (b-c) Cytokine production of CNS-infiltrating endogenous or 2D2 CD4+ T cells at the peak of EAE disease was determined by intracellular cytokine staining following brief ex vivo PMA/ionomycin re-stimulation. (d) Mean clinical scores in Tbx21f/f or Tbx21f/f CD4-Cre+ mice receiving 2D2 WT TH17 cells (7.5 × 106). NS, P > 0.05; *, P < 0.01 (two-tailed Student’s t-test (b,c) or two-way ANOVA (d)). Data are combined from two independent experiments (a-c; n = 9, 10 mice per group) or three independent experiments (d; n = 15, 16 mice per group).

Supplementary Figure 2 T-bet expression in dendritic cells is not required for EAE induction by 2D2 WT TH17 cells.

(a) Intracellular cytokine staining of CNS-infiltrating 2D2 CD4+ T cells (CD4+Vβ11+) from Tbx21f/f or Tbx21f/f CD11c-Cre+ mice following adoptive transfer of 7.5 × 106 2D2 WT TH17 cells. CNS-infiltrating cells were harvested at the peak of EAE disease (day 15-17 post-transfer) and re-stimulated ex vivo with PMA/ionomycin. (b) Mean clinical scores in Tbx21f/f or Tbx21f/f CD11c-Cre+ mice which received 2D2 WT TH17 cells (7.5 × 106). NS, P > 0.05 (two-way ANOVA). Data are combined from two independent experiments (a; mean ± s.e.m. of n = 10, 12 mice per group) or three independent experiments (b; mean ± s.e.m. of n = 17, 19 mice per group).

Supplementary Figure 3 Efficiency of NK cell deletion in anti-NK1.1-treated mice.

Depletion of NK cells in WT (BL6) mice by anti-NK1.1 (clone PK136) treatment. 500 μg of αNK1.1 antibody per dose, or an equivalent volume of PBS, was injected intravenously via the tail vein into WT mice, beginning 5 days prior to the adoptive transfer of 2D2 WT TH17 cells and continuing until 16 days post-transfer (indicated by red arrows). On the day of the adoptive transfer of 2D2 WT TH17 cells (day 0), peripheral lymphoid and non-lymphoid tissues were harvested from representative mice, and NK cells were quantified to assess the efficacy of depletion. On day 21 post-transfer, CNS-infiltrating cells were harvested from representative mice to assess the efficacy and duration of NK cell depletion in the CNS. Data are representative of three independent experiments; numbers indicate the frequency of CD3−NKp46+ cells among total live cells.

Supplementary Figure 4 NK cell deficiency in Eomesf/f NKp46-Cre+mice.

(a-b) Frequency and absolute numbers of conventional NK cells (TCRβ−NKp46+NK1.1+IL-7Rα−) in lymphoid and non-lymphoid tissues of Eomesf/f or Eomesf/f NKp46-Cre+mice 12-14 days after active immunization with MOG35-55/CFA and pertussis toxin. Data are representative of two independent experiments (n = 3 mice per group).

Supplementary Figure 5 IFN-γ is required for the activation/maturation of meningeal APCs.

(a) Mean clinical scores of Ifng−/− and WT mice, which received 7.5 × 106 2D2 WT TH17 cells. (b) Absolute number of 2D2 CD4+ T cells (CD4+Vβ11+) in the spinal cord meninges and CNS parenchyma of WT or Ifng−/− mice as quantitated by flow cytometry. (c) Absolute number of CD206+ perivascular macrophages (PVMs), myeloid DCs (mDCs), inflammatory monocytes (iMO) and neutrophils in the meninges of WT or Ifng−/− mice as quantitated by flow cytometry (Supplementary Fig. 6 for gating strategy). (d) Flow cytometric analyses of the maturation markers on meningeal antigen presenting cells in WT or Ifng−/− mice following the adoptive transfer of 7.5 × 106 2D2 WT TH17 cells. Activation of spinal cord meningeal antigen presenting cells was determined by staining perivascular macrophages and myeloid-derived dendritic cells with antibodies to MHC ClassII (I-A/I-E) molecules, CD80 and ICAM1. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 (two-way ANOVA (a) or two-tailed Student’s t-test (b-d)). Data are representative of two independent experiments (a; mean ± s.e.m. of n = 10 mice per group) or combined from two independent experiments (b-d; mean ± SEM of n = 10 mice per group).

Supplementary Figure 6 Gating strategy for resident and infiltrating meningeal APCs.

Spinal cord meningeal cells were harvested at the peak of EAE disease (day 17 - 22 post-transfer), gated on live CD45+ cells, and further identified as follows: perivascular macrophages (Thy1.2− CD11b+ Ly6C− Ly6G−F4/80+ CD206+), myeloid-derived dendritic cells (Thy1.2−MHCII+CD11c+CD11b+), inflammatory monocytes (Thy1.2− CD11b+Ly6C+ Ly6G−) and neutrophils (Thy1.2− CD11b+Ly6C−Ly6G+).

Supplementary Figure 7 NKp46+ ILCs are dispensable for activation of meningeal APCs.

(a) Absolute number of CD206+ perivascular macrophages (PVMs), myeloid DCs (mDCs), inflammatory monocytes (iMO) and neutrophils in the meninges of Tbx21f/f or Tbx21f/f NKp46-Cre+ mice as quantitated by flow cytometry (Supplementary Fig. 6 for gating strategy). (b) Flow cytometric analyses of the activation markers on meningeal antigen presenting cells in Tbx21f/f or Tbx21f/f NKp46-Cre+ mice following the adoptive transfer of 7.5 × 106 2D2 WT TH17 cells. Activation of spinal cord meningeal antigen presenting cells was determined by staining perivascular macrophages and myeloid-derived dendritic cells with antibodies to MHC ClassII (I-A/I-E) molecules, CD80 and ICAM1. Naïve healthy WT (BL6) mice were used to assess the steady-state expression of maturation markers. Expression levels are presented as mean fluorescence intensity (MFI) of staining (b); data are combined from 3 independent experiments with 11 mice per group.

Supplementary Figure 8 T-bet-dependent NKp46+ ILCs are not required for GM-CSF production by IL-17A-producing 2D2 CD4+ T cells.

Intracellular cytokine staining of 2D2 CD4+ T cells (CD4+Vβ11+) isolated from the meninges and CNS parenchyma of Tbx21f/f or Tbx21f/f NKp46-Cre+ mice following adoptive transfer of 7.5 × 106 2D2 WT TH17 cells. CNS-infiltrating cells were harvested at the peak of EAE disease (day 17-22 post-transfer) and re-stimulated ex vivo with PMA/ionomycin prior to staining. Bar graphs present mean ± s.e.m of cytokine producing 2D2 CD4+ T cells isolated from the spinal cord meninges and parenchyma of Tbx21f/f or Tbx21f/f NKp46-Cre+ mice. NS, P > 0.05; *, P < 0.01 (two-tailed Student’s t-test). Data are combined from 2 independent experiments (n = 6, 8 mice per group).

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Kwong, B., Rua, R., Gao, Y. et al. T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation. Nat Immunol 18, 1117–1127 (2017). https://doi.org/10.1038/ni.3816

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