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Abstract Number: 1582

RORγt Inhibition Selectively Targets Pathogenic Subsets of Human iNKT and γδ-T Cells Enriched in Spondyloarthritis While Preserving Tissue Protective IL-22 Responses

Koen Venken1,2, Mark Labadia3, Kathleen Hoyt3, Anita Wayne3, Robert Hughes3, Michael Turner3, Dustin Smith4, Christian Harcken4, Tine Decruy5,6, Joseph Wahle7, Chao-Ting Wang3, Peggy Jacques8, Sofie Van Gassen9, Gaëlle Varkas10, Heleen Cypers10, Filip van Den Bosch11, Yvan Saeys9, Gerald Nabozny12 and Dirk Elewaut13,14, 1Department of Rheumatology, Faculty of Medicine and Health Sciences, Laboratory for Molecular Immunology and Inflammation,, Ghent, Belgium, 2VIB Inflammation Research Center, Ghent University, Ghent, Belgium, 3Research and Development Boehringer-Ingelheim, Ridgefield, CT, 4Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, 5Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium, Ghent, Belgium, 6VIB Inflammation Research Center, Ghent, Belgium, 7Department of Immunology and respiratory discovery research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, 8Ghent University Hospital, Ghent, Belgium, 9Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium, 10Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, VIB, Ghent University and Ghent University Hospital, Ghent, Belgium, 11Rheumatology, Ghent University Hospital, Gent, Belgium, 12[email protected], Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, 13VIB Inflammation Research Center, University of Ghent, Ghent, Belgium, 14Department of Rheumatology, Laboratory for molecular immunology and inflammation, Ghent, Belgium

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: IL-23, innate immunity and spondylarthritis

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Session Information

Date: Monday, November 6, 2017

Title: Spondyloarthropathies and Psoriatic Arthritis – Pathogenesis, Etiology Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

Dysregulated IL-23/IL-17 responses have been linked to a myriad of inflammatory diseases including psoriasis, psoriatic arthritis and other forms of spondyloarthritides (SpA). IL-23/IL-17 inflammation is controlled by RORγt, the key Thelper17 (Th17) cell transcriptional regulator. RORγt is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and γδ-T cells, but how this contributes to inflammatory disorders such as SpA is still unclear.

Methods:

Blood samples were obtained from 27 healthy control subjects and 33 patients with newly diagnosed SpA (following ASAS 2010 criteria). Synovial fluid (SF) was obtained from patients with an active knee synovitis and an indication for aspiration. Patients were treatment naïve or under treatment with a NSAID and/or DMARD (Methotrexate, Sulfasalazin), but naïve for treatment with biologicals at the time op sampling. PBMC and SFMC were isolated from patient samples and were directly analyzed by multi-color flow cytometry for analysis of iNKT cells (CD3+6B11+ TCRVβ11+), γδ-T cells (CD3+TCRγδ+) and CD161+ and CD161- conventional Tconv (T cells excluded from innate-like T cells). Rorc and Il-23r mRNA expression on specific T cell subsets was measured by means of PrimeFlow RNA Assays. Flow cytometric data were analysed by standard gating procedures using FlowJo software and further explored by FlowSOM, a novel method for computational multi-color flow cytometry. Furthermore, sorted γδ-T cells and iNKT cells were cultured in the presence of αGalCer (for iNKT) or aCD3/aCD28Ab (γδ-T cells) with addition of IL-23, IL-1β, TGFB1 and IL-2 (IL-23 cocktail) in the presence or absence of a RORγt inhibitor. Cytokine production of cells was determined by intracellular flow cytometric staining or in supernatants by multiplex protein assays (MSD). In addition, phenotypical analyses were done by qPCR with specific primers for IL-23R, IL-17A and F, IL-22 and RORC.

Results:

Here, we describe a unique population of RORγt+T-betloPLZF– iNKT and TCRγδ-hi T cells (γδ-T cells with a high expression of the γδTCR), present in healthy peripheral blood. iNKT and γδ-hi T cells showed marked IL-23 mediated Th17-like immune responses and are clearly enriched within inflamed joints. Interestingly, in depth metacluster analyses by FlowSOM iterations showed skewing of novel iNKT cell subsets, already detectable in the blood of SpA patients. RORγt blocked Th17 cell function and inhibited IL-17 production while surprisingly preserved IL-22 production by iNKT and γδ-T cells. Further FlowSOM analyses showed that RORγt inhibition impacts distinctive IL-17+ iNKT cell subsets while preserving IL-22 subsets.

Conclusion:

Overall, these findings highlight a unique diversity of human RORγt+ innate-like T cells and underscore the potential of RORγt antagonism to modulate aberrant Type 17 responses.


Disclosure: K. Venken, None; M. Labadia, Boehringer Ingelheim, 3; K. Hoyt, Boehringer Ingelheim, 3; A. Wayne, Boehringer Ingelheim, 3; R. Hughes, Boehringer Ingelheim, 3; M. Turner, Boehringer Ingelheim, 3; D. Smith, Boehringer Ingelheim, 3; C. Harcken, Boehringer Ingelheim, 3; T. Decruy, None; J. Wahle, None; C. T. Wang, Boehringer Ingelheim, 3; P. Jacques, None; S. Van Gassen, None; G. Varkas, None; H. Cypers, None; F. van Den Bosch, None; Y. Saeys, None; G. Nabozny, Boehringer Ingelheim, 3; D. Elewaut, Scientific Research Flanders; Research Council Ghent University; Interuniversity Attraction Pole., 2,Boehringer Ingelheim; Pfizer; UCB; Merck; Novartis; Janssen; Abbvie, 5.

To cite this abstract in AMA style:

Venken K, Labadia M, Hoyt K, Wayne A, Hughes R, Turner M, Smith D, Harcken C, Decruy T, Wahle J, Wang CT, Jacques P, Van Gassen S, Varkas G, Cypers H, van Den Bosch F, Saeys Y, Nabozny G, Elewaut D. RORγt Inhibition Selectively Targets Pathogenic Subsets of Human iNKT and γδ-T Cells Enriched in Spondyloarthritis While Preserving Tissue Protective IL-22 Responses [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/ror%ce%b3t-inhibition-selectively-targets-pathogenic-subsets-of-human-inkt-and-%ce%b3%ce%b4-t-cells-enriched-in-spondyloarthritis-while-preserving-tissue-protective-il-22-responses/. Accessed .
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