Thrombospondin‐1‐dependent immune regulation by transforming growth factor‐ β 2 ‐exposed antigen‐presenting cells

Summary An important role of transforming growth factor‐ β ( TGF ‐ β ) in the development of regulatory T cells is well established. Although integrin‐mediated activation of latent TGF ‐ β 1 is considered essential for the induction of regulatory T (Treg) cells by antigen‐presenting cells ( APC s), such an activation mechanism is not applicable to the TGF ‐ β 2 isoform, which lacks an integrin‐binding RGD sequence in its latency‐associated peptide. Mucosal and ocular tissues harbour TGF ‐ β 2 ‐expressing APC s involved in Treg induction. The mechanisms that regulate TGF ‐ β activation in such APC s remain unclear. In this study, we demonstrate that murine APC s exposed to TGF ‐ β 2 in the environment predominantly increase expression of TGF ‐ β 2 . Such predominantly TGF ‐ β 2 ‐expressing APC s use thrombospondin‐1 ( TSP ‐1) as an integrin‐independent mechanism to activate their newly synthesized latent TGF ‐ β 2 to induce Foxp3 + Treg cells both in vitro and in vivo . Expression of Treg induction by TGF ‐ β 2 ‐expressing APC s is supported by a TSP ‐1 receptor, CD 36, which facilitates activation of latent TGF ‐ β 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 ‐ β 2 ‐expressing APC s similar to those located at mucosal and ocular sites. These findings introduce the integrin‐independent mechanism of TGF ‐ β activation as an integral part of peripheral immune tolerance associated with TGF ‐ β 2 ‐expressing tissues.