Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
J Immunol. 2010 Oct 15;185(8):4691-7. doi: 10.4049/jimmunol.1001133. Epub 2010 Sep 15.
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.
血小板反应蛋白-1（TSP-1）是一种具有免疫调节特性的基质细胞糖蛋白，包括抑制 APC 功能。我们在移植研究中发现，TSP-1 可抑制 T 细胞同种致敏，从而抑制免疫排斥。角膜是 TSP-1 的丰富来源，通过比较角膜移植中野生型（WT）与 TSP-1 缺失同种移植物，可揭示这一点。与仅 50%的 WT 同种异体移植物被排斥相比，几乎所有的 TSP-1 缺失同种异体移植物都屈服于排斥。这种效应反映在供体来源的 APC 上，与 WT APC 相比，它们在移植宿主中具有明显更强的同种致敏能力。在 MLR 中进一步证实，与 WT APC 相比，TSP-1 缺失 APC 刺激导致更高的增殖水平和更强的 IFN-γ（但不是 IL-10）阳性 T 细胞。此外，在炎症期间，TSP-1 缺失 APC 上检测到 MHC Ⅱ类和 B7 成熟标志物的表达增强。TSP-1 缺失 APC 移植后，CCR7 的表达增加进一步匹配其淋巴结迁移增强。因此，我们得出结论，APC 来源的 TSP-1 抑制了它们同种致敏 T 细胞的能力，这种调节源于它们对成熟形式的抵抗力。未来针对 APC 上调 TSP-1 的策略可能有效促进同种异体移植物的存活。
