Thrombospondin-1 derived from APCs regulates their capacity for allosensitization.
Thrombospondin (TSP)-1 is a matricellular glycoprotein with immunoregulatory properties, which include inhibition of APC function. We show in transplantation that TSP-1 inhibits T cell allosensitization and consequently suppresses immune rejection. This was revealed by comparing wild-type (WT) versus TSP-1 null allografts in corneal transplantation, as the cornea is a rich source of TSP-1. Compared with only 50% of rejected WT allografts, nearly all TSP-1 null allografts succumbed to rejection. This effect was reflected by donor-derived APCs, which exhibited a distinctively greater capacity for allosensitization in transplanted hosts. Corroborated in MLRs, greater proliferation levels and robust IFN-γ (but not IL-10)-positive T cells resulted from stimulation by TSP-1 null APCs relative to WT ones. Moreover, enhanced expression of MHC class II and B7 maturation markers were detected on TSP-1 null APCs during inflammation. Increased expression of CCR7 was further matched by enhanced lymph node migration of TSP-1 null APCs posttransplantation. We therefore conclude that APC-derived TSP-1 suppresses their capacity to allosensitize T cells, and this regulation stems from their resistance to taking on a mature form. Future strategies targeting APCs for TSP-1 upregulation may thus be effective in promoting allograft survival.
Saban
Daniel R
DR
Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
Bock
Felix
F
Chauhan
Sunil K
SK
Masli
Sharmila
S
Dana
Reza
R
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016039:Corneal Transplantation; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019700:Thrombospondin 1 / Q000276:immunology* / Q000378:metabolism; D014181:Transplantation Immunology / Q000276:immunology*
D019700:Thrombospondin 1