The Tyrosine Kinase Tec Regulates Effector Th17 Differentiation, Pathogenicity, and Plasticity in T-Cell-Driven Intestinal Inflammation

Frontiers in Immunology, vol. 12, pp. 750466

Abstract

T helper (Th) 17 cells are not only key in controlling infections mediated by extracellular bacteria and fungi but are also triggering autoimmune responses. Th17 cells comprise heterogeneous subsets, some with pathogenic functions. They can cease to secrete their hallmark cytokine IL-17A and even convert to other T helper lineages, a process known as transdifferentiation relying on plasticity. Both pathogenicity and plasticity are tightly linked to IL-23 signaling. Here, we show that the protein tyrosine kinase Tec is highly induced in Th17 cells. Th17 differentiation was enhanced at low interleukin-6 (IL-6) concentrations in absence of Tec, which correlates with increased STAT3 phosphorylation and higher Il23r expression. Therefore, we uncovered a function for Tec in the IL-6 sensing via STAT3 by CD4+ T cells, defining Tec as a fine-tuning negative regulator of Th17 differentiation. Subsequently, by using the IL-17A fate mapping mouse combined with in vivo adoptive transfer models, we demonstrated that Tec not only restrained effector Th17 differentiation but also pathogenicity and plasticity in a T-cell intrinsic manner. Our data further suggest that Tec regulates inflammatory Th17-driven immune responses directly impacting disease severity in a T-cell-driven colitis model. Notably, consistent with the in vitro findings, elevated levels of the IL-23 receptor (IL-23R) were observed on intestinal pre- and postconversion Th17 cells isolated from diseased Tec−/− mice subjected to adoptive transfer colitis, highlighting a fundamental role of Tec in restraining IL-23R expression, likely via the IL-6-STAT3 signaling axis. Taken together, these findings identify Tec as a negative regulator of Th17 differentiation, pathogenicity, and plasticity, contributing to the mechanisms which help T cells to orchestrate optimal immune protection and to restrain immunopathology.

Authors 14

1. Lisa Sandner

   Medical University of Vienna

   Affiliation as printed

   Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria

2. Marlis Alteneder

   Medical University of Vienna

   Affiliation as printed

   Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria

3. Ci Zhu

   Medical University of Vienna

   Affiliation as printed

   Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria

   Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria

4. Anastasiya Hladik

   Medical University of Vienna

   Affiliation as printed

   Department of Medicine 1, Research Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria

5. Sandra Högler

   University of Veterinary Medicine Vienna

   Affiliation as printed

   Unit of Laboratory Animal Pathology, Department for Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria

6. Ramona Rîca

   Medical University of Vienna

   Affiliation as printed

   Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria

7. Lars W van Greuningen Aachen Department of Medical Biochemistry Leiden Institute of Chemistry, Leiden

   Leiden University

   Affiliation as printed

   Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden, Netherlands

8. Omar Sharif

   Medical University of Vienna

   Affiliation as printed

   Center for Physiology and Pharmacology, Institute for Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria

   Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria

9. Shinya Sakaguchi

   Medical University of Vienna

   Affiliation as printed

   Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria

10. Sylvia Knapp

    Medical University of Vienna

    Affiliation as printed

    Department of Medicine 1, Research Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria

11. Lukas Kenner

    University of Veterinary Medicine Vienna · Center For Biomarker Research In Medicine · Medical University of Vienna

    Affiliation as printed

    Center for Biomarker Research in Medicine (CBmed), Graz, Austria

    Christian Doppler Laboratory for Applied Metabolomics (CDL-AM), Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria

    Department of Pathology, Medical University of Vienna, Vienna, Austria

    Division of Experimental and Translational Pathology, Department of Pathology, Medical University Vienna, Vienna, Austria

    Unit of Laboratory Animal Pathology, Department for Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria

12. Michael A Trauner

    Medical University of Vienna

    Affiliation as printed

    Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria

13. Wilfried Ellmeier

    Medical University of Vienna

    Affiliation as printed

    Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria

14. Nicole Boucheron corresponding

    Medical University of Vienna

    Affiliation as printed

    Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria