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

Abstract

Transforming growth factor β (TGFβ)-treated antigen-presenting cells (APC) pulsed with antigen induce tolerance in mice, i.e. inhibition of IFN-γ 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 TGFβ2 and antigen (TGFβ-treated APC) transferred tolerance to naive recipients. Interestingly, TGFβ -treated APC from class II knockout mice were unable to induce tolerance in wild-type mice, whereas wild-type TGFβ-treated APC could induce tolerance in CD8 knockout mice. TGFβ was detected in cultures of lymphoid cells from mice injected with TGFβ-treated APC, and treatment with anti-TGFβ antibody in vivo impaired tolerance induction. TGFβ 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 TGFβ-treated APC in naive mice, and tolerance appears to be mediated by a mechanism involving TGFβ. © 2004 Wiley-VCH Verlag GmbH & Co. KGaA.