Thrombospondin orchestrates the tolerance-promoting properties of TGFβ-treated antigen-presenting cells

Eye-derived antigen-presenting cells (APCs) are known to contribute to the immune privilege status of the eye by inducing a form of peripheral tolerance that deviates T(h)1 type of pro-inflammatory immune responses. Similar systemic tolerance can also be induced by non-ocular APCs exposed to transforming growth factor beta (TGF beta) in vitro. Such APCs were found to express enhanced levels of thrombospondin (TSP)-1, an extracellular matrix (ECM) protein. In this report, we analyzed the significance of TSP-1 in conferring tolerance-inducing properties on APCs. While TSP-treated APCs matched TGF beta-treated APCs in their functional ability to induce systemic tolerance, a deficiency of TSP-1 or its receptor CD36 prevented APCs from becoming tolerogenic in response to TGF beta. Exogenous TSP-1 restored tolerogenic ability of TGF beta-treated TSP-1 null APCs. Both TGF beta-treated TSP-1 null and CD36 knockout APCs failed to inhibit IL-12 secretion. Furthermore, TGF beta-treated TSP-1 null APCs, unlike similarly treated wild-type APCs, failed to increase secretion of active TGF beta. Similar to TGF beta, TSP could also up-regulate expression of MIP-2, TGF beta 2 and tumor necrosis factor alpha-all of which are required for tolerance induced by TGF beta-treated APCs. We conclude that TSP-1, an ECM protein induced by TGF beta treatment, orchestrates the changes in APC functional programs that equip these cells to promote tolerance of the eye-derived type.