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Nature communications
01 02, 2019;10 (1): 9.

RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients.

Koen Venken, Peggy Jacques, Céline Mortier, Mark E Labadia, Tine Decruy, Julie Coudenys, Kathleen Hoyt, Anita L Wayne, Robert Hughes, Michael Turner, Sofie Van Gassen, Liesbet Martens, Dustin Smith, Christian Harcken, Joseph Wahle, Chao-Ting Wang, Eveline Verheugen, Nadia Schryvers, Gaëlle Varkas, Heleen Cypers, Ruth Wittoek, Yves Piette, Lieve Gyselbrecht, Serge Van Calenbergh, Filip Van den Bosch, Yvan Saeys, Gerald Nabozny, Dirk Elewaut
Author Information
  1. Koen Venken: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium. koen.venken@ugent.be.
  2. Peggy Jacques: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.
  3. Céline Mortier: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.
  4. Mark E Labadia: Research and Development Boehringer-Ingelheim, 175 Briar Ridge Road, Ridgefield, CT, 06877, USA.
  5. Tine Decruy: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.
  6. Julie Coudenys: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.
  7. Kathleen Hoyt: Research and Development Boehringer-Ingelheim, 175 Briar Ridge Road, Ridgefield, CT, 06877, USA.
  8. Anita L Wayne: Research and Development Boehringer-Ingelheim, 175 Briar Ridge Road, Ridgefield, CT, 06877, USA.
  9. Robert Hughes: Research and Development Boehringer-Ingelheim, 175 Briar Ridge Road, Ridgefield, CT, 06877, USA.
  10. Michael Turner: Research and Development Boehringer-Ingelheim, 175 Briar Ridge Road, Ridgefield, CT, 06877, USA.
  11. Sofie Van Gassen: VIB Inflammation Research Center, Ghent University, Technologiepark 71, 9052, Ghent, Belgium.
  12. Liesbet Martens: VIB Inflammation Research Center, Ghent University, Technologiepark 71, 9052, Ghent, Belgium. ORCID
  13. Dustin Smith: Research and Development Boehringer-Ingelheim, 175 Briar Ridge Road, Ridgefield, CT, 06877, USA.
  14. Christian Harcken: Research and Development Boehringer-Ingelheim, 175 Briar Ridge Road, Ridgefield, CT, 06877, USA.
  15. Joseph Wahle: Research and Development Boehringer-Ingelheim, 175 Briar Ridge Road, Ridgefield, CT, 06877, USA.
  16. Chao-Ting Wang: Research and Development Boehringer-Ingelheim, 175 Briar Ridge Road, Ridgefield, CT, 06877, USA.
  17. Eveline Verheugen: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.
  18. Nadia Schryvers: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.
  19. Gaëlle Varkas: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.
  20. Heleen Cypers: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.
  21. Ruth Wittoek: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.
  22. Yves Piette: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.
  23. Lieve Gyselbrecht: ASZ Aalst, Merestraat 80, 9300, Aalst, Belgium.
  24. Serge Van Calenbergh: Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9052, Gent, Belgium. ORCID
  25. Filip Van den Bosch: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.
  26. Yvan Saeys: VIB Inflammation Research Center, Ghent University, Technologiepark 71, 9052, Ghent, Belgium.
  27. Gerald Nabozny: Research and Development Boehringer-Ingelheim, 175 Briar Ridge Road, Ridgefield, CT, 06877, USA.
  28. Dirk Elewaut: Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium. dirk.elewaut@ugent.be.
PMID: 30602780 DOI: 10.1038/s41467-018-07911-6

Abstract

Dysregulated IL-23/IL-17 responses have been linked to psoriatic arthritis and other forms of spondyloarthritides (SpA). RORγt, the key Thelper17 (Th17) cell transcriptional regulator, is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and γδ-T cells, but their contribution to SpA is still unclear. Here we describe the presence of particular RORγtT-betPLZF iNKT and γδ-hi T cell subsets in healthy peripheral blood. RORγt iNKT and γδ-hi T cells show IL-23 mediated Th17-like immune responses and were clearly enriched within inflamed joints of SpA patients where they act as major IL-17 secretors. SpA derived iNKT and γδ-T cells showed unique and Th17-skewed phenotype and gene expression profiles. Strikingly, RORγt inhibition blocked γδ17 and iNKT17 cell function while selectively sparing IL-22 subsets. Overall, our findings highlight a unique diversity of human RORγt T cells and underscore the potential of RORγt antagonism to modulate aberrant type 17 responses.

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MeSH Term

Case-Control Studies
Humans
Interleukin-17
Natural Killer T-Cells
Nuclear Receptor Subfamily 1, Group F, Member 3
Receptors, Antigen, T-Cell, gamma-delta
Receptors, Interleukin
Spondylarthritis
T-Lymphocyte Subsets

Chemicals

IL23R protein, human
Interleukin-17
Nuclear Receptor Subfamily 1, Group F, Member 3
RORC protein, human
Receptors, Antigen, T-Cell, gamma-delta
Receptors, Interleukin
Journal Article Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000026 (RORγt inhibition selectively targets IL-17 producing human iNKT and γδ-T cells enriched in Spondyloarthritis while preserving IL-22 responses)

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