Regulatory T cells in experimental arthritis

Background

It is now generally accepted that central and peripheral immune tolerance is in part mediated by the action of suppressor cells. In particular, CD4⁺ T cells coexpressing CD25 (CD4⁺CD25⁺ regulatory T cells [T_reg]) have been shown crucial for the prevention of autoimmunity in several animal models. We investigated the role of this cell population in murine antigen-induced arthritis, a well-characterized experimental model of human rheumatoid arthritis.

Methods

For this purpose, we used two different approaches. First, the depletion of CD25-expressing cells in vivo using a monoclonal antibody against this molecule, and second, the transfer of purified CD4⁺CD25⁺ T_reg from naive donors into arthritic mice.

Results

Depletion of CD25-expressing cells resulted in a clinical and histological aggravation of arthritis. The increased severity of arthritis was due to a lack of T_reg cells, since transfer of purified CD4⁺CD25⁺cells from naive donors into depleted animals ameliorated the clinical signs of arthritis. The aggravated arthritis in depleted mice was accompanied by exaggerated humoral (serum IgG) and cellular (ELISPOT) immune responses against the inducing antigen (methylated bovine serum albumin) and to cartilage matrix constituents (collagen type I, collagen type II, proteoglycans). Thus, CD4⁺CD25⁺ T_reg cells may regulate the severity of arthritis by adjusting the systemic immune responsiveness to arthritis-related antigens. Furthermore, adoptive transfer of purified CD4⁺CD25⁺ T_reg cells, isolated from naive mice, into arthritic animals resulted invariably in a marked decrease of the severity of arthritis. Especially with use of in vitro preactivated T_reg cells, this effect could be achieved with very low cell numbers (1 × 10⁵cells per animal). Analysis of cellular and humoral immune responses in the recipients did not shown signs of systemic immunosuppression. Local immunoregulatory effects of these cells are possibly involved, but their exact mechanism of action is hitherto unknown.

Conclusions

Taken together, these data implicate a pivotal role of CD4⁺CD25⁺ immunoregulatory T cells in experimental arthritis, and it can be hypothesized that they are a new diagnostic or prognostic tool for rheumatoid arthritis patients. Hopefully, enhancement of their function may be beneficial for these patients and represents a new therapeutic strategy in autoimmune diseases.