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Open Access Research article

CD4+CD25+/highCD127low/- regulatory T cells are enriched in rheumatoid arthritis and osteoarthritis joints—analysis of frequency and phenotype in synovial membrane, synovial fluid and peripheral blood

Babak Moradi1*, Philipp Schnatzer1, Sébastien Hagmann1, Nils Rosshirt1, Tobias Gotterbarm1, Jan Philippe Kretzer1, Marc Thomsen2, Hanns-Martin Lorenz3, Felix Zeifang1 and Theresa Tretter3

Author Affiliations

1 University Clinic of Heidelberg, Clinic for Orthopedics and Trauma Surgery, Schlierbacher Landstr. 200a, 69118 Heidelberg, Germany

2 Klinikum Baden-Baden, Lilienmattstraße 5, 76530 Baden-Baden, Germany

3 University Clinic of Heidelberg, Department of Medicine V Div. of Rheumatology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

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Arthritis Research & Therapy 2014, 16:R97  doi:10.1186/ar4545

Published: 17 April 2014

Abstract

Introduction

CD4+CD25+/highCD127low/- regulatory T cells (Tregs) play a crucial role in maintaining peripheral tolerance. Data about the frequency of Tregs in rheumatoid arthritis (RA) are contradictory and based on the analysis of peripheral blood (PB) and synovial fluid (SF). Because Tregs exert their anti-inflammatory activity in a contact-dependent manner, the analysis of synovial membrane (SM) is crucial. Published reports regarding this matter are lacking, so we investigated the distribution and phenotype of Tregs in concurrent samples of SM, SF and PB of RA patients in comparison to those of osteoarthritis (OA) patients.

Methods

Treg frequency in a total of 40 patients (18 RA and 22 OA) matched for age and sex was assessed by flow cytometry. Functional status was assessed by analysis of cell surface markers representative of activation, memory and regulation.

Results

CD4+ T cells infiltrate the SM to higher frequencies in RA joints than in OA joints (P = 0.0336). In both groups, Tregs accumulate more within the SF and SM than concurrently in PB (P < 0.0001). Relative Treg frequencies were comparable in all compartments of RA and OA, but Treg concentration was significantly higher in the SM of RA patients (P = 0.025). Both PB and SM Tregs displayed a memory phenotype (CD45RO+RA-), but significantly differed in activation status (CD69 and CD62L) and markers associated with Treg function (CD152, CD154, CD274, CD279 and GITR) with only minor differences between RA and OA.

Conclusions

Treg enrichment into the joint compartment is not specific to inflammatory arthritis, as we found that it was similarly enriched in OA. RA pathophysiology might not be due to a Treg deficiency, because Treg concentration in SM was significantly higher in RA. Synovial Tregs represent a distinct phenotype and are activated effector memory cells (CD62L-CD69+), whereas peripheral Tregs are resting central memory cells (CD62L+CD69-).