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Expression of IL-17F is associated with non-pathogenic Th17 cells

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Abstract

IL-17A and IL-17F share the highest sequence homology of the IL-17 family and signal via the same IL-17RA/RC receptor heterodimer. To better explore the expression of these two cytokines, we used a double reporter mouse strain (IL-17DR mice), where IL-17A expressing cells are marked by enhanced green fluorescent protein (eGFP) while red fluorescence protein (RFP) reports the expression of IL-17F. In steady state, we found that Th17 and γδ T cells only expressed IL-17A, while IL-17F expression was restricted to CD8 T cells (Tc17) and innate lymphoid cells (ILC type 3) of the gut. In experimental autoimmune encephalomyelitis, the vast majority of CNS-infiltrating Th17 cells expressed IL-17A but not IL-17F. In contrast, anti-CD3-induced, TGF-β-driven Th17 cells in the gut expressed both of these IL-17 cytokines. In line with this, in vitro differentiation of Th17 cells in the presence of IL-1β led primarily to IL-17A expressing T cells, while TGF-β induced IL-17F co-expressing Th17 cells. Our results suggest that expression of IL-17F is associated with non-pathogenic T cells, pointing to a differential function of IL-17A versus IL-17F.

Key messages

  • Naïve mice: CD4+ T cells and γδ T cells express IL-17A, and Tc17 cells express IL-17F. Gut ILC3 show differential expression of IL17A and F.

  • Th17 differentiation with TGF-β1 induces IL-17A and F, whereas IL-1β induced cells expressing IL-17A.

  • Th17 cells in EAE in CNS express IL-17A only.

  • Gut Th17 cells induced by anti-CD3 express IL-17A and F together as skin γδ T cells of IMQ-treated mice.

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Acknowledgements

We thank Bettina Kalt, Petra Adams, and Michaela Blanfeld for excellent technical assistance. We acknowledge Steffanie Bürger and Ina Schäfer from the Institute for Molecular Biology in Mainz for excellent assistance with the flow cytometry. We thank Svenja Schüler for help with statistical data representation. We are grateful to Richard Flavell and Chen Dong to share with us the reporter mouse lines used in this study. This work was supported by the Deutsche Forschungsgemeinschaft SFB/TR-128 to F.C.K. and A.W. and by SFB/TR-156 to A.W., A.D., and F.C.K.

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Author notes

  1. Andreas Diefenbach

    Present address: Institute of Microbiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Hindenburgdamm 27, 12203, Berlin, Germany

  2. Florian C. Kurschus

    Present address: Department of Dermatology, Heidelberg University Hospital, 69120, Heidelberg, Germany

  3. Florian C. Kurschus and Ari Waisman contributed equally.

  4. Yilang Tang and Konrad Gronke contributed equally.

Authors and Affiliations

  1. University Medical Center of the Johannes Gutenberg University Mainz, Institute for Molecular Medicine, 55131, Mainz, Germany

    Florian Wanke, Yilang Tang, Sabrina Klebow, Sonja Moos, Judith Hauptmann, Arthi Shanmugavadivu, Tommy Regen, Ilgiz A. Mufazalov, Lauren A. Gabriel, Sonja Reißig, Florian C. Kurschus & Ari Waisman

  2. Immunology, Inflammation & Infectious Diseases (I3), Discovery and Translational Area, Roche Pharma Research & Early Development (pRED), 4070, Basel, Switzerland

    Florian Wanke

  3. Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg University Mainz, 55131, Mainz, Germany

    Konrad Gronke & Andreas Diefenbach

  4. Institute of Microbiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Hindenburgdamm 27, 12203, Berlin, Germany

    Konrad Gronke

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  1. Florian Wanke
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Correspondence to Florian C. Kurschus or Ari Waisman.

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All experiments with mice were carried out in accordance with the guidelines of the Central Animal Facility Institution of Mainz and in accordance with relevant laws and guidelines with permission by the state Rhineland-Palatinate (animal experimentation applications (TVA) nos. G13-1-099 and G12-1-057). The approval process contained an ethical committee meeting instated by the Landesuntersuchungsamt Rheinland-Pfalz.

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Wanke, F., Tang, Y., Gronke, K. et al. Expression of IL-17F is associated with non-pathogenic Th17 cells. J Mol Med 96, 819–829 (2018). https://doi.org/10.1007/s00109-018-1662-5

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