Journal Article

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

Verheugen, Eveline, Venken, Koen, Cypers, Heleen, Hoyt, Kathleen, Martens, Liesbet, Van den Bosch, Filip, Harcken, Christian, Jacques, Peggy, Gyselbrecht, Lieve, Wahle, Joseph, Van Calenbergh, Serge, Mortier, Céline, Hughes, Robert, Nabozny, Gerald, Smith, Dustin, Wittoek, Ruth, Wayne, Anita L., Labadia, Mark E., Varkas, Gaëlle, Decruy, Tine, Piette, Yves, Coudenys, Julie, Wang, Chao-Ting, Van Gassen, Sofie, Saeys, Yvan, Elewaut, Dirk, Turner, Michael, Schryvers, Nadia

2019

Overview

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 RORγt + T-bet lo PLZF − 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. The role of innate T cell subsets in the pathogenesis of spondyloarthritis (SpA) is not well understood. Here, the authors examine the role of invariant natural killer T (iNKT) and γδ-T cells in SpA and show that disease-derived iNKT and γδ-T cells have unique and Th17-skewed phenotype and gene expression profiles within inflamed joints.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/21 / 13/31 / 38/77 / 38/91 / 631/250/1619/554 / 631/250/256 / 631/250/808 / 692/4023/1670/2766 / Arthritis / Case-Control Studies / Gene expression / Helper cells / Humanities and Social Sciences / Humans / Inflammation / Inflammatory diseases / Interleukin 17 / Interleukin 22 / Interleukin 23 / Interleukin-17 - metabolism / Joint diseases / Lymphocytes / Lymphocytes T / multidisciplinary / Natural killer cells / Natural Killer T-Cells - metabolism / Nuclear Receptor Subfamily 1, Group F, Member 3 - antagonists & inhibitors / Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism / Patients / Peripheral blood / Phenotypes / Psoriatic arthritis / Receptors, Antigen, T-Cell, gamma-delta - metabolism / Receptors, Interleukin - metabolism / Rheumatic diseases / Science / Science (multidisciplinary) / Spondylarthritis - immunology / T-Lymphocyte Subsets - metabolism / Transcription