Alloantigenicity of human endothelial cells. II. Analysis of interleukin 2 production and proliferation by T cells after contact with allogeneic endothelia.
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.
Adams
P W
PW
Department of Surgery, Ohio State University College of Medicine, Columbus 43210.
Lee
H S
HS
Ferguson
R M
RM
Orosz
C G
CG
D017252:CD3 Complex / Q000032:analysis; D004730:Endothelium, Vascular / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D017252:CD3 Complex; D007376:Interleukin-2; D015375:Receptors, Interleukin-2