CONTACT-DEPENDENT ENDOTHELIAL CLASS-II HLA GENE ACTIVATION-INDUCED BYNK CELLS IS MEDIATED BY IFN-GAMMA-DEPENDENT AND IFN-GAMMA-INDEPENDENTMECHANISMS

NK lymphocytes adhere avidly to allogeneic endothelial cells (ECs) and induce their membrane expression of MHC class II Ags in vitro. Endoth elial class II expression augments EC-driven CD4(+) T cell proliferati on in vitro, and may amplify T cell recruitment and clonal expansion i n vivo. Using an ex vivo lymphocyte-skin organ coculture model, NK cel ls could be found lining and inducing class II HLA on microvessel endo thelium. Using neutralizing anti-IFN-gamma and anti-IFN-gamma receptor Abs, a spectrum of IFN-gamma dependence was observed for NK-mediated EC HLA-DR induction at the membrane and transcriptional levels, from n egligible to moderate. Transwell experiments displayed that direct NK- EC contact is required, and Ab inhibition studies indicated that the b eta 2 integrin-ICAM-1 pathway(s) is critical in the generation of thes e responses. The use of HLA-DR alpha promoter constructs in transient transfection assays demonstrated that the highly conserved X and S tra nscription boxes are required in both IFN-gamma- and NK-mediated gene activation. As expected, because of the receptor species specificity, human IFN-gamma did not induce HLA-DR alpha promoter constructs transf ected in Chinese hamster ovary cells, whereas NK cells did. Taken toge ther, these results indicate that human allogeneic NK lymphocytes indu ce EC class II HLA gene activation and membrane expression in an adhes ion-dependent, IFN-gamma-independent fashion and suggest that, in conc ert with any IFN-gamma-dependent component, this induction could repre sent an efficient mode of endothelial activation and immune amplificat ion in vivo.