Thrombospondin-1-dependent immune regulation by transforming growth factor-β2-exposed antigen-presenting cells

An important role of transforming growth factor-beta (TGF-beta) in the development of regulatory T cells is well established. Although integrin-mediated activation of latent TGF-beta(1) is considered essential for the induction of regulatory T (Treg) cells by antigen-presenting cells (APCs), such an activation mechanism is not applicable to the TGF-beta(2) isoform, which lacks an integrin-binding RGD sequence in its latency-associated peptide. Mucosal and ocular tissues harbour TGF-beta(2)-expressing APCs involved in Treg induction. The mechanisms that regulate TGF-beta activation in such APCs remain unclear. In this study, we demonstrate that murine APCs exposed to TGF-beta(2) in the environment predominantly increase expression of TGF-beta(2). Such predominantly TGF-beta(2)-expressing APCs use thrombospondin- 1 (TSP-1) as an integrin-independent mechanism to activate their newly synthesized latent TGF-beta(2) to induce Foxp3(+) Treg cells both in vitro and in vivo. Expression of Treg induction by TGF-beta(2)-expressing APCs is supported by a TSP-1 receptor, CD36, which facilitates activation of latent TGF-beta during antigen presentation. Our results suggest that APC-derived TSP-1 is essential for the development of an adaptive regulatory immune response induced by TGF-beta(2)-expressing APCs similar to those located at mucosal and ocular sites. These findings introduce the integrin-independent mechanism of TGF-beta activation as an integral part of peripheral immune tolerance associated with TGF-beta(2)-expressing tissues.