UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Synovial Regulatory T Cells Occupy a Discrete TCR Niche in Human Arthritis and Require Local Signals To Stabilize FOXP3 Protein Expression

Bending, D; Giannakopoulou, E; Lom, H; Wedderburn, LR; (2015) Synovial Regulatory T Cells Occupy a Discrete TCR Niche in Human Arthritis and Require Local Signals To Stabilize FOXP3 Protein Expression. Journal of Immunology , 195 (12) pp. 5616-5624. 10.4049/jimmunol.1500391. Green open access

[thumbnail of Synovial Regulatory T Cells Occupy a Discrete TCR Niche in Human Arthritis and Require Local Signals To Stabilize FOXP3 Protein Expression.pdf]
Preview
Text
Synovial Regulatory T Cells Occupy a Discrete TCR Niche in Human Arthritis and Require Local Signals To Stabilize FOXP3 Protein Expression.pdf - Published Version

Download (1MB) | Preview

Abstract

Although there is great interest in harnessing the immunosuppressive potential of FOXP3(+) regulatory T cells (Tregs) for treating autoimmunity, a sizeable knowledge gap exists regarding Treg fate in human disease. In juvenile idiopathic arthritis (JIA) patients, we have previously reported that atypical CD25(+)FOXP3(-) Treg-like cells uniquely populate the inflamed site. Intriguingly, their proportions relative to CD25(+)FOXP3(+) Tregs associate with arthritis course, suggesting a role in disease. The ontogeny of these FOXP3(-) Treg-like cells is, however, unknown. In this study, we interrogated clonal relationships between CD4(+) T cell subsets in JIA, using high-throughput TCR repertoire analysis. We reveal that FOXP3(+) Tregs possess highly exclusive TCRβ usage from conventional T cells, in blood, and also at the inflamed site, where they are clonally expanded. Intriguingly, the repertoires of FOXP3(+) Tregs in synovial fluid are highly overlapping with CD25(+)FOXP3(-) Treg-like cells, indicating fluctuations in FOXP3 expression in the inflamed joint. Furthermore, cultured synovial Tregs rapidly downregulated FOXP3 protein (but not mRNA), and this process was prevented by addition of synovial fluid from JIA patients, through an IL-6-independent mechanism. Our findings suggest that most Tregs arise from a separate lineage from conventional T cells, and that this repertoire divergence is largely maintained under chronic inflammatory conditions. We propose that subsequent Treg expansions at the inflamed site creates an environment that leads to competition for limited resources within the synovium, resulting in the destabilization of FOXP3 expression in some Tregs.

Type: Article
Title: Synovial Regulatory T Cells Occupy a Discrete TCR Niche in Human Arthritis and Require Local Signals To Stabilize FOXP3 Protein Expression
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.4049/jimmunol.1500391
Publisher version: http://dx.doi.org/10.4049/jimmunol.1500391
Language: English
Additional information: Copyright © 2015 The Authors This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1474845
Downloads since deposit
80Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item