Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4(+)CD45RC(-) cells and CD4(+)CD8(-) thymocytes

Previous studies have shown that induction of autoimmune diabetes by adult thymectomy and split dose irradiation of PVG.RT1(u) rats can be prevented b y their reconstitution with peripheral CD4(+)CD45RC(-)TCR-alpha/beta(+)RT6( +) cells and CD4(+)CD8(-) thymocytes from normal syngeneic donors. These da ta provide evidence for the role of regulatory T cells in the prevent-ion o f a tissue-specific autoimmune disease but the mode of action of these cell s has not been reported previously. In this study, autoimmune thyroiditis w as induced in PVG.RT1(c) rats using a similar protocol of thymectomy and ir radiation. Although a cell-mediated mechanism has been implicated in the pa thogenesis of diabetes in PVG.RT1(u) rats, development of thyroiditis is in dependent of CD8(+) T cells and is characterized by high titers of immunogl obulin (Ig)G1 antithyroglobulin antibodies, indicating a major humoral comp onent in the pathogenesis of disease. As with autoimmune diabetes in PVG.RT 1(u) rats, development of thyroiditis was prevented by the transfer of CD4( +)CD45RC(-) and CD4(+)CD8(-) thymocytes from normal donors but not by CD4()CD45RC(+) peripheral T cells. We now show that transforming growth factor (TGF)-beta and interleukin (IL)-4 both play essential roles in the mechanis m of this protection since administration of monoclonal antibodies that blo ck the biological activity of either of these cytokines abrogates the prote ctive effect of the donor cells in the recipient rats. The prevention of bo th diabetes and thyroiditis by CD4(+)CD45RC(-) peripheral cells and CD4(+)C D8(-)thymocytes therefore does not support the view that the mechanism of r egulation involves a switch from a T helper cell type 1 (Th1) to a Th2-like response, but rather relies upon a specific suppression of the autoimmune responses involving TGF-beta and IL-4. The observation that the same two cy tokines were implicated in the protective mechanism, whether thymocytes or peripheral cells were used to prevent autoimmunity, strongly suggests that the regulatory cells from both sources act in the same way and that the thy mocytes are programmed in the periphery for their protective role. The impl ications of this result with respect to immunological homeostasis are discu ssed.