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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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.).

Author information

Author notes

    • Brandon Kwong
    •  & Rejane Rua

    These authors contributed equally to this work.

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.

Competing interests

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

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https://doi.org/10.1038/ni.3816

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