Thrombospondin orchestrates the tolerance-promoting properties of TGFbeta-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 (TGFbeta) 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 TGFbeta-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 TGFbeta. Exogenous TSP-1 restored tolerogenic ability of TGFbeta-treated TSP-1 null APCs. Both TGFbeta-treated TSP-1 null and CD36 knockout APCs failed to inhibit IL-12 secretion. Furthermore, TGFbeta-treated TSP-1 null APCs, unlike similarly treated wild-type APCs, failed to increase secretion of active TGFbeta. Similar to TGFbeta, TSP could also up-regulate expression of MIP-2, TGFbeta2 and tumor necrosis factor alpha-all of which are required for tolerance induced by TGFbeta-treated APCs. We conclude that TSP-1, an ECM protein induced by TGFbeta treatment, orchestrates the changes in APC functional programs that equip these cells to promote tolerance of the eye-derived type.
Masli
Sharmila
S
Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA. smasil@vision.eri.harvard.edu
Turpie
Bruce
B
Streilein
J Wayne
JW
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology*; D018955:CD36 Antigens / Q000276:immunology; D005109:Extracellular Matrix / Q000276:immunology; D005434:Flow Cytometry; D007108:Immune Tolerance; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D018417:Th1 Cells / Q000276:immunology; D019700:Thrombospondin 1 / Q000096:biosynthesis / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation
D018955:CD36 Antigens; D007370:Interferon Type I; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D018664:Interleukin-12