T-Regulatory Cells From Patients With Rheumatoid Arthritis Retain Suppressor Functions In Vitro

Rheumatoid arthritis (RA) is a chronic disease of connective tissue caused by intolerance to self-antigens. Regulatory T cells (Tregs) are key players in maintaining autotolerance through a variety of suppressor mechanisms. RA is generally believed to develop due to disorders in Tregs; however, there is no consensus on this issue. Thus, the present study focused on phenotypical analysis of Treg cells and their ability to suppress CD4(+) and CD8(+) cell proliferation. The present study used peripheral blood samples from 21 patients with RA and 22 healthy donors. The CD25(+)FoxP3(+) subpopulation of Tregs was analyzed using flow cytometry to evaluate the expression of CTLA-4, PD-L1, HLA-DR, CCR4, CD86 and RORyt. Tregs suppressor activity was calculated in terms of suppression of the proliferation of CD4(+) and CD8(+) lymphocytes in vitro. Suppressor activity of the total Treg population did not differ between patients with RA and healthy donors. However, the patients had elevated CD25(lo)FoxP3(+) levels and lower CD25(hi)FoxP3(+) levels; in addition, they had more activated Tregs expressing PD-L1, HLA-DR, CCR4 and CD86. The surface expression of CTLA-4 was below the reference level. The patients also had transitional FoxP3(+)RORyt(+) cells and elevated CD4(+)RORyt(+) levels, which were highly correlated with disease activity. These results show that in RA, Treg cells are activated and have an immunosuppressive activity. However, it is the transitional FoxP3(+)RORyt(+) cells and increased CD4(+)RORyt(+) percentages in peripheral blood that appear to be associated with the pathological conversion of some Treg cells into Th-17. This process appears to be key in RA pathogenesis.