Tissue-specific homing receptor mediates lymphocyte adhesion to cytokine-stimulated lymph node high endothelial...

Lymphocytes bind to high endothelial venule (HEV) cells as the first step in the migration of these cells into lymph nodes (LN) and Peyer's patches (PP). In this study we isolated and cultured HEV cells from rat LN and investigated the effects of cytokines on the adhesiveness of these cells for lymphocytes. The results showed that lymphocytes from thoracic duct, spleen and LN adhered preferentially to the cultured LN HEV cells compared to cells isolated from the thymus and bone marrow. The adhesiveness of LN HEV cells for thoracic duct lymphocytes (TDL) was significantly increased in a dose- and time-dependent manner by pretreatment of the HEV cells with tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) or interleukin-4 (IL-4). In contrast, pretreatment of HEV cells with IL-1, IL-6 or IL-7 did not alter the capacity of LN HEV cells to adhere lymphocytes. Furthermore, incubation of LN HEV cells with suboptimal doses of TNF and IL-4, IFN-gamma and IL-4, or TNF-alpha and IFN-gamma increased significantly the endothelial adhesiveness. Interestingly, although IL-1 alone did not promote the adhesiveness of HEV cells, the cytokine synergized with suboptimal doses of IL-4 and TNF-alpha to increase the adhesiveness. The adhesion of TDL to non-stimulated and IL-4-stimulated LN HEV cells could be blocked specifically by treatment of lymphocytes with the LN homing-receptor-specific A.11.5 monoclonal antibody (mAb). In contrast, lymphocytes pretreated with the PP-homing receptor-specific 1B.2.6 mAb or the antileucocyte common antigen (OX1) mAb adhered normally to the HEV cells. Taken together, these results indicate that the baseline and cytokine-stimulated bindings between lymphocytes and LN HEV cells are mediated by adhesive mechanisms that regulate lymphocyte migration into LN in vivo and provide strong evidence that cytokines are central mediators of organ-specific lymphocyte migration.