Adams P W, Lee H S, Ferguson R M, Orosz C G
Department of Surgery, Ohio State University College of Medicine, Columbus 43210.
Transplantation. 1994 Jan;57(1):115-22. doi: 10.1097/00007890-199401000-00019.
In organ allograft recipients, the first point of contact between the host immune system and the graft alloantigens is the graft vascular endothelia. Our previous experiments have established that there are multiple pathways by which T cells can be activated in vitro by endothelial alloantigens. In this report, we focus on the first of these pathways: the direct activation of T cells by endothelial MHC class I molecules. Using conventional mixed cell cultures and limiting dilution analyses, we demonstrate that "resting" allogeneic human umbilical vein endothelial cells (HUVEC) stimulate IL-2 production, but not proliferation of purified CD3+ PBMC. Transwell experiments demonstrate that soluble suppressive factors are not responsible for the lack of proliferation. Instead, they suggest that the production of growth factors, such as IL-2, is suboptimal in this system. Indeed, submitogenic concentrations of IL-2 synergize with HUVEC to induce strong T cell proliferative responses. This proliferation is associated with a detectable increase in T cell IL-2R expression, which is not apparent after stimulation with HUVEC or IL-2 alone. In conjunction with previous data, these observations characterize the first direct pathway of endothelia-induced T cell activation. Via this pathway, a small number of CD8+ T cells can be activated by the allogeneic MHC class I molecules displayed by resting allogeneic endothelial cells. This activation results in the elaboration of IL-2, among other things, in concentrations that are too small to promote IL-2R up-regulation, and thus T cell proliferation. Proliferation readily occurs if sufficient IL-2 is available in the environment to overcome this cytokine deficit. These studies suggest that endothelial MHC class I alloantigens are mildly antigenic to a small subset of T cells. However, in an inflammatory environment that is rich in cytokines and growth factors, these endothelial alloantigens may become potent direct stimulators of T cell activation and clonal expansion.
在器官同种异体移植受者中，宿主免疫系统与移植物同种异体抗原的首个接触点是移植物血管内皮细胞。我们之前的实验已证实，T细胞可通过多种途径在体外被内皮同种异体抗原激活。在本报告中，我们聚焦于这些途径中的第一条：内皮细胞MHC I类分子对T细胞的直接激活。使用传统混合细胞培养和有限稀释分析，我们证明“静止”的同种异体人脐静脉内皮细胞（HUVEC）可刺激IL-2产生，但不会刺激纯化的CD3 + PBMC增殖。Transwell实验表明，可溶性抑制因子并非导致缺乏增殖的原因。相反，它们表明生长因子（如IL-2）的产生在该系统中未达到最佳水平。实际上，亚致有丝分裂浓度的IL-2与HUVEC协同作用可诱导强烈的T细胞增殖反应。这种增殖与T细胞IL-2R表达的可检测增加相关，而单独用HUVEC或IL-2刺激后这种增加并不明显。结合先前的数据，这些观察结果描绘了内皮细胞诱导T细胞激活的首个直接途径。通过该途径，少数CD8 + T细胞可被静止同种异体内皮细胞展示的同种异体MHC I类分子激活。这种激活除其他外会导致IL-2的分泌，其浓度过小以至于无法促进IL-2R上调，从而无法促进T细胞增殖。如果环境中有足够的IL-2来克服这种细胞因子缺乏，增殖就很容易发生。这些研究表明，内皮细胞MHC I类同种异体抗原对一小部分T细胞具有轻度抗原性。然而，在富含细胞因子和生长因子的炎症环境中，这些内皮同种异体抗原可能成为T细胞激活和克隆扩增的有效直接刺激物。
