Abstract
IntroductionCD4+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.MethodsTreg 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.ResultsCD4+ 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.ConclusionsTreg 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-).
Highlights
CD4+CD25+/highCD127low/− regulatory T cells (Tregs) play a crucial role in maintaining peripheral tolerance
rheumatoid arthritis (RA) pathophysiology might not be due to a Regulatory T cell (Treg) deficiency, because Treg concentration in synovial membrane (SM) was significantly higher in RA
Our data show that CD4+ T cells are significantly enriched in the SM of RA patients when compared to OA
Summary
CD4+CD25+/highCD127low/− regulatory T cells (Tregs) play a crucial role in maintaining peripheral tolerance. The pathology of the disease is characterized by disturbed immune regulation with predominance of inflammatory cells on the one hand and defective peripheral immune tolerance on the other [1] These immunopathologic events occur predominantly within the joints and in the synovial membrane (SM) as the main site of mononuclear cell infiltration. CD4+ T cells comprise a large proportion of the inflammatory cells recruited into the RA synovium and contribute significantly to synovial inflammation [2] In contrast to these inflammatory CD4+ T cells, another T-cell subset, known as naturally occurring regulatory T cells (Tregs), has been shown to play an essential role in establishing the balance between proand anti-inflammatory mechanisms in the periphery and maintaining self-tolerance, both in rodents and in humans [1,3,4,5].
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