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Abstract

T helper 9 (TH9) cells are important for the development of inflammatory and allergic diseases. The TH9 transcriptional network converges signals from cytokines and antigen presentation but is incompletely understood. Here, we identified TL1A, a member of the TNF superfamily, as a strong inducer of mouse and human TH9 differentiation. Mechanistically, TL1A induced the expression of the transcription factors BATF and BATF3 and facilitated their binding to the Il9 promoter leading to enhanced secretion of IL-9. BATF- and BATF3-deficiencies impaired IL-9 secretion under TH9 and TH9-TL1A-polarizing conditions. In vivo, using a T-cell transfer model, we demonstrated that TL1A promoted IL-9-dependent, TH9 cell-induced intestinal and lung inflammation. Neutralizing IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Batf3−/− TH9-TL1A cells induced reduced inflammation and cytokine expression in vivo compared to WT cells. Our results demonstrate that TL1A promotes TH9 cell differentiation and function and define a role for BATF3 in T-cell-driven mucosal inflammation.

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Acknowledgements

This work was supported by the NIH (DK056328 to S.R.T.) and the F. Widjaja Foundation (S.R.T. and K.S.M.). Anita Vibsig Neutzsky-Wulff received postdoctoral fellowships from The Carlsberg Foundation (Denmark) and the Lundbeck Foundation (Denmark). Jordan Nunnelee received a Student Research Award by the Crohn’s and Colitis Foundation of America. The Cedars-Sinai MIRIAD IBD Biobank is supported by the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, NIH/NIDDK grants P01 DK046763, U01 DK062413, and The Leona M and Harry B Helmsley Charitable Trust.

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Author notes

    • Masato Tsuda

    Present address: Food and Physiological Functions Laboratory, College of Bioresource Sciences, Nihon University, 1866 Kameino Fujisawa-shi Kanagawa, Tokyo, 252-0880, Japan

Affiliations

  1. F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    • Masato Tsuda
    • , Hussein Hamade
    • , Lisa S. Thomas
    • , Brenda C. Salumbides
    • , Alka A. Potdar
    • , Michelle H. Wong
    • , Jordan S. Nunnelee
    • , Jasmine T. Stamps
    • , Anita Vibsig Neutzsky-Wulff
    • , Robert J. Barrett
    • , Stephan R. Targan
    •  & Kathrin S. Michelsen
  2. Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    • Robert J. Barrett
  3. Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    • Yizhou Wang
    • , Jie Tang
    •  & Vincent A. Funari

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Contributions

M.T., H.H., L.T., M.W., B.S., M.W., J.N., J.S., A.N.-W., R.B., Y.W., J.T., V.F., and K.M. performed experiments, analyzed data, and critically reviewed the manuscript. A.P., J.T., and Y.W. performed RNA-Seq data analysis. M.T., S.T., and K.M. designed the experiments. M.T. and K.M. wrote the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Kathrin S. Michelsen.

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DOI

https://doi.org/10.1038/s41385-018-0122-4