Pettigrew G J, Lovegrove E, Bradley J A, Maclean J, Bolton E M
Department of Surgery, University of Glasgow, Scotland, United Kingdom.
J Immunol. 1998 Aug 1;161(3):1292-8.
Recent studies in the rat have identified a role for T cell-dependent alloantibody in rejection of MHC class I-disparate allografts. RT1Aa-disparate PVG.R8 heart grafts are rejected acutely in naive, and hyperacutely in sensitized, PVG.RTIu recipients by CD4 T cell-dependent alloantibody. Here, we examined the T cell Ag recognition pathways responsible and show that direct injection into skeletal muscle of plasmid DNA, encoding a water-soluble form of the RT1Aa MHC class I heavy chain (pcmu-tAa), stimulates IgG2b cytotoxic alloantibody and markedly accelerates rejection of PVG.R8 heart grafts (median survival time 2 days). pcmu-tAa injection did not induce CTL to Aa, arguing against direct allorecognition of soluble Aa. Treatment with mAbs confirmed that the alloimmune response to pcmu-tAa injection depended on CD4, not CD8, T cells. Priming T cells for indirect allorecognition by injection of 15-mer peptides spanning the alpha1 and alpha2 domains of Aa failed to stimulate anti-Aa Ab but caused an accelerated Ab response to a PVG.R8 heart and a modest acceleration in graft rejection (median survival time 4 days). These results suggest that both soluble MHC class I and allopeptides prime CD4 T cells by the indirect pathway, but that soluble class I is a more effective immunogen for humoral alloimmunity because its tertiary protein structure provides B cell epitopes. We propose that priming humoral alloimmunity, like CTL priming, requires recognition of intact MHC on donor cells, but essential T cell help can be provided by CD4 T cells recognizing allogeneic class I exclusively by the indirect pathway.
最近在大鼠身上进行的研究已确定，T细胞依赖性同种异体抗体在MHC I类不同的同种异体移植物排斥反应中发挥作用。在未致敏的PVG.RTIu受体中，RT1Aa不同的PVG.R8心脏移植物会被急性排斥，而在致敏受体中则会被超急性排斥，这是由CD4 T细胞依赖性同种异体抗体介导的。在此，我们研究了负责的T细胞抗原识别途径，并表明将编码水溶性形式的RT1Aa MHC I类重链（pcmu-tAa）的质粒DNA直接注射到骨骼肌中，可刺激IgG2b细胞毒性同种异体抗体，并显著加速PVG.R8心脏移植物的排斥反应（中位存活时间为2天）。注射pcmu-tAa并未诱导针对Aa的CTL，这表明可溶性Aa不存在直接的同种异体识别。用单克隆抗体进行的处理证实，对pcmu-tAa注射的同种免疫反应依赖于CD4而非CD8 T细胞。通过注射跨越Aa的α1和α2结构域的15聚体肽来启动T细胞进行间接同种异体识别，未能刺激产生抗Aa抗体，但导致对PVG.R8心脏的抗体反应加速，以及移植物排斥反应适度加速（中位存活时间为4天）。这些结果表明，可溶性MHC I类和同种异体肽均通过间接途径启动CD4 T细胞，但可溶性I类对于体液同种免疫而言是一种更有效的免疫原，因为其三级蛋白质结构提供了B细胞表位。我们提出，启动体液同种免疫，如同启动CTL一样，需要识别供体细胞上完整的MHC，但识别同种I类的CD4 T细胞仅通过间接途径提供的必需T细胞辅助也可发挥作用。
