Gallon L, Watschinger B, Murphy B, Akalin E, Sayegh M H, Carpenter C B
Department of Medicine, Brigham and Women's Hospital, Harvard Medical school, Boston, Massachusetts 02115.
Transplantation. 1995 Feb 27;59(4):612-6.
There is evidence that T cells can "directly" recognize intact allo-MHC molecules on the surface of allogeneic stimulator or target cells, and/or "indirectly" recognize processed allo-MHC peptides presented by self antigen-presenting cells (APCs). We and others have recently demonstrated that in vivo-primed rat CD4+ T cells recognize and proliferate to specific polymorphic amino acid sequences when presented as MHC allopeptides by self APCs. Studies on the mechanisms of indirect T cell recognition of alloantigen are now reported. First, we studied the immunogenicity of 4 synthetic polymorphic class II MHC allopeptides representing full-length sequences of the hypervariable domains of RT1.Du beta (DR or I-E-like) in several responder strains: LEW (RT1(l)), ACI (RT1a), BUF (RT1b), BN (RT1n), and control syngeneic WF (RT1u) strains. Immunogenicity of the individual 25mer allopeptides varied in the different responder strains, indicating that self-restricted T cell recognition of allo-MHC peptides is determined not only by polymorphisms, but also by the responder MHC genotype. Self-restricted CD4+ T cell recognition of processed allo-MHC peptides has been shown to occur during acute skin and cardiac allograft rejection, and there is evidence that this pathway may play an important role in initiating and amplifying the immune response to allografts. T cells from LEW animals primed in vivo by WF (RT1u) vascularized renal allografts were capable of proliferating to the RT1.Du beta peptides as early as 3 days postengraftment, when presented by self APCs. We then tested the effects of various immunosuppressive drugs on self-restricted primed T cell proliferative response to an immunogenic MHC allopeptide in vitro. Methylprednisolone, cyclosporine, and FK506 inhibited the proliferative response of RT1.Du beta 2-primed LEW T cells in a dose-dependent fashion. In addition, a single injection of cyclosporine (25 mg/kg i.m.) to LEW recipients of WF renal allografts on the day of transplantation completely abolished the proliferative response of in vivo-primed T cells to RT1.Du beta 2, indicating the susceptibility of the indirect pathway of allorecognition to conventional immunosuppressive drugs.
有证据表明，T细胞可以“直接”识别同种异体刺激细胞或靶细胞表面完整的同种异体MHC分子，和/或“间接”识别由自身抗原呈递细胞（APC）呈递的经加工的同种异体MHC肽。我们和其他人最近证明，体内致敏的大鼠CD4+T细胞在由自身APC呈递为MHC异源肽时，能够识别特定的多态性氨基酸序列并发生增殖。现将关于间接T细胞识别同种异体抗原机制的研究报告如下。首先，我们研究了4种合成的多态性II类MHC异源肽的免疫原性，这些异源肽代表了RT1.Duβ（DR或I-E样）高变区的全长序列，在几种应答品系中进行研究：LEW（RT1(l)）、ACI（RT1a）、BUF（RT1b）、BN（RT1n）以及同基因对照WF（RT1u）品系。单个25聚体异源肽的免疫原性在不同应答品系中有所不同，这表明自身限制的T细胞对同种异体MHC肽的识别不仅由多态性决定，还由应答者的MHC基因型决定。已证明，在急性皮肤和心脏同种异体移植排斥反应期间会发生自身限制的CD4+T细胞对经加工的同种异体MHC肽的识别，并且有证据表明该途径可能在启动和放大对同种异体移植的免疫反应中起重要作用。早在移植后3天，当由自身APC呈递时，经WF（RT1u）血管化肾脏同种异体移植在体内致敏的LEW动物的T细胞就能对RT1.Duβ肽发生增殖。然后，我们在体外测试了各种免疫抑制药物对自身限制的致敏T细胞对免疫原性MHC异源肽增殖反应的影响。甲基强的松龙、环孢素和FK506以剂量依赖的方式抑制RT1.Duβ2致敏的LEW T细胞的增殖反应。此外，在移植当天对接受WF肾脏同种异体移植的LEW受体单次注射环孢素（25mg/kg，肌肉注射）完全消除了体内致敏T细胞对RT1.Duβ2的增殖反应，表明同种异体识别的间接途径对传统免疫抑制药物敏感。
