TGF-β in transplantation tolerance

TGF-β is a cytokine required for the induction and maintenance of transplantation tolerance in animal models. TGF-β mediates anti-inflammatory effects by acting on many immune cell-types. Central for transplantation tolerance is the role for TGF-β in the induction of Foxp3 and regulatory capacity in CD4+ T cells. Recently, however, the general anti-inflammatory role of TGF-β in CD4+ T cell polarization was questioned by the discovery that, in the presence of inflammatory cytokines such as IL-6 or IL-1, TGF-β drives the differentiation of Th17 cells associated with transplant rejection. A better understanding of the factors determining TGF-β production and activation, Foxp3 induction and Treg stability is vital for the development of tolerogenic strategies in transplantation.

► TGF-β signalling to T cells and Foxp3 induction is required for transplantation tolerance.
► Foxp3 is induced by TGF-β via SMAD acting on enhancer I and the stability of Tregs is regulated by epigenetic mechanisms.
► TGF-β also contributes to the polarization of Th17 cells that are involved in transplant rejection.
► Treg need to express STAT3 and produce IL-10 to specifically suppress Th17 responses.
► The availability of TGF-β for T cell polarization might be regulated at delivery and activation steps rather than production.