Koen Venken: Modulatory roles of Tregs in gut vs joint inflammation in TNF-driven spondyloarthritis скачать в хорошем качестве

Koen Venken: Modulatory roles of Tregs in gut vs joint inflammation in TNF-driven spondyloarthritis

Full title: Understanding the role of T cells in SpA: Distinct immune modulatory roles of regulatory T cells in gut versus joint inflammation in TNF-driven spondyloarthritis 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 concomitant arthritis. RNA-sequencing (RNA-seq) and flow cytometry was performed on inflamed gut and joint samples and tissue-derived Tregs from TNF∆ARE mice. In situ hybridization of TNF and its receptors (TNFR) was applied to human SpA gut biopsies. Soluble(s) TNFR levels were measured in serum of mice and SpA patients and controls. Treg function was explored by in vitro co-cultures and in vivo by conditional Treg depletion. 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 mRNA levels were noted in TNF∆ARE/+ mice leading to increased sTNFR2 release. Likewise, sTNFR2 levels were higher in SpA patients 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. Taken together, 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. Prof. Koen Venken has a longstanding interest in T cell biology with a primary focus on translational research. He completed his PhD at the Biomedical Research Institute of the University of Hasselt (Belgium) and Maastricht (The Netherlands), looking into the role of human Tregs in multiple sclerosis. For his post-doctoral training he moved to the University of Ghent (Belgium), becoming acquainted with human and experimental research in the field of Rheumatology. For this he received grant support from the Research Foundation - Flanders (FWO) and VLAIO (Flanders Innovation & Entrepreneurship). Dr. Venken is currently a senior Staff Scientist at the Flemish Institute for Biotechnology (VIB)- Center for Inflammation Research and appointed as an assistant professor at the Faculty of Medicine and Health Sciences of Ghent University. His current research focuses on the role of innate-like and regulatory T cells in the area of chronic inflammatory diseases, specifically joint and mucosal tissue inflammation.