Distinct immune modulatory roles of regulatory T cells in gut versus joint inflammation in TNF-driven spondyloarthritis
Venken, Koen; Jarlborg, Matthias; Decruy, Tine; Mortier, Céline; Vlieghe, Carolien; Gilis, Elisabeth; De Craemer, Ann-Sophie; Coudenys, Julie; Cambré, Isabelle; Fleury, Devan; Klimowicz, Alexander; Van den Bosch, Filip; Hoorens, Anne; Lobaton, Triana; de Roock, Sytze; Sparwasser, Tim; Nabozny, Gerald; Jacques, Peggy; Elewaut, Dirk
(2023) Annals of the Rheumatic Diseases, volume 82, issue 8, pp. 1076 - 1090
(Article)
Abstract
OBJECTIVES: Gut and joint inflammation commonly co-occur in spondyloarthritis (SpA) which strongly restricts therapeutic modalities. The immunobiology underlying differences between gut and joint immune regulation, however, is poorly understood. We therefore assessed the immunoregulatory role of CD4 +FOXP3 + regulatory T (Treg) cells in a model of Crohn's-like ileitis and
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concomitant arthritis. METHODS: RNA-sequencing and flow cytometry was performed on inflamed gut and joint samples and tissue-derived Tregs from tumour necrosis factor (TNF) ∆ARE mice. In situ hybridisation of TNF and its receptors (TNFR) was applied to human SpA gut biopsies. Soluble TNFR (sTNFR) levels were measured in serum of mice and patients with SpA and controls. Treg function was explored by in vitro cocultures and in vivo by conditional Treg depletion. RESULTS: Chronic TNF exposure induced several TNF superfamily (TNFSF) members (4-1BBL, TWEAK and TRAIL) in synovium and ileum in a site-specific manner. Elevated TNFR2 messenger RNA levels were noted in TNF ∆ARE/+ mice leading to increased sTNFR2 release. Likewise, sTNFR2 levels were higher in patients with SpA with gut inflammation and distinct from inflammatory and healthy controls. Tregs accumulated at both gut and joints of TNF ∆ARE mice, yet their TNFR2 expression and suppressive function was significantly lower in synovium versus ileum. In line herewith, synovial and intestinal Tregs displayed a distinct transcriptional profile with tissue-restricted TNFSF receptor and p38MAPK gene expression. CONCLUSIONS: These data point to profound differences in immune-regulation between Crohn's ileitis and peripheral arthritis. Whereas Tregs control ileitis they fail to dampen joint inflammation. Synovial resident Tregs are particularly maladapted to chronic TNF exposure.
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Keywords: T-lymphocyte subsets, arthritis, experimental, spondyloarthritis, General Biochemistry,Genetics and Molecular Biology, Rheumatology, Immunology and Allergy, Immunology
ISSN: 0003-4967
Publisher: BMJ Publishing Group
Note: Funding Information: KV is supported by FWO-Vl (Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Grant 3E014310), VLAIO (Flanders Innovation & Entrepreneurship, HBC.2016.0622) and a FOREUM research grant. DE is supported by FWO-Vl (3G079911, 3G0C7719, 3G051016), Research Council of Ghent University (01GA3217) and a FWO Excellence of Science (EOS) Grant (EOS 30480119). FvdB is supported by a Special Research Fund (01G03122) from Ghent University. TS was supported by DFG/CRC355 (project A4). Publisher Copyright: © Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.
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