International Immunology Advance Access originally published online on March 28, 2006
International Immunology 2006 18(5):689-699; doi:10.1093/intimm/dxl006
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Thrombospondin orchestrates the tolerance-promoting properties of TGFß-treated antigen-presenting cells
1 Schepens Eye Research Institute and
2 Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
Correspondence to: S. Masli; E-mail: smasli{at}vision.eri.harvard.edu
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 Th1 type of pro-inflammatory immune responses. Similar systemic tolerance can also be induced by non-ocular APCs exposed to transforming growth factor ß (TGFß) 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 TGFß-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 TGFß. Exogenous TSP-1 restored tolerogenic ability of TGFß-treated TSP-1 null APCs. Both TGFß-treated TSP-1 null and CD36 knockout APCs failed to inhibit IL-12 secretion. Furthermore, TGFß-treated TSP-1 null APCs, unlike similarly treated wild-type APCs, failed to increase secretion of active TGFß. Similar to TGFß, TSP could also up-regulate expression of MIP-2, TGFß2 and tumor necrosis factor 
—all of which are required for tolerance induced by TGFß-treated APCs. We conclude that TSP-1, an ECM protein induced by TGFß treatment, orchestrates the changes in APC functional programs that equip these cells to promote tolerance of the eye-derived type.
Keywords: antigen presentation/processing, monocytes/macrophages, tolerance
Transmitting editor: W. Strober
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