Mechanisms of tolerance induced by TGFβ-treated APC:: CD4 regulatory T cells prevent the induction of the immune response possibly through a mechanism involving TGFβ

Transforming growth factor beta (TGFbeta)-treated antigen-presenting cells (APC) pulsed with antigen induce tolerance in mice, i.e. inhibition of IFN-gamma production and delayed type hypersensitivity response. Although evidence suggests that regulatory T cells are involved, their mechanism of action is currently unknown and is the subject of the present study. Both CD4 and CD8 splenic T cells from mice injected i.v. with adherent thioglycolate-elicited peritoneal exudate cells cultured with TGFbeta(2) and antigen (TGFbeta-treated APC) transferred tolerance to naive recipients. Interestingly, TGFbeta-treated APC from class 11 knockout mice were unable to induce tolerance in wild-type mice, whereas wild-type TGFbeta-treated APC could induce tolerance in CD8 knockout mice. TGFbeta was detected in cultures of lymphoid cells from mice injected with TGFbeta-treated APC, and treatment with anti-TGFbeta antibody in vivo impaired tolerance induction. TGFbeta appeared to be involved in both the development of CD4 regulatory T cells and the effector function of the CD4 regulatory T cells. In summary, the important findings in this study are that CD4, and not CD8, regulatory T cells are required for tolerance induced by TGFbeta-treated APC in naive mice, and tolerance appears to be mediated by a mechanism involving TGFbeta.