Disaccharides generated from heparan sulphate or heparin modulate chemokine-induced T-cell adhesion to extracellular matrix

We have found previously that disaccharides (DS) enzymatically generated fr om heparin or heparan sulphate can modulate tumour necrosis factor-alpha (T NF-alpha) secretion from immune cells in vitro and cell-mediated immune rea ctions in vivo. Here, we show that such DS can modulate the adhesion and mi gration of human T cells. We found that certain heparin- and heparan sulpha te derived DS induced, in a dose-dependent manner, the adhesion of human T cells to both extracellular matrix (ECM) and immobilized fibronectin (FN); maximal T-cell adhesion occurred with 1 ng/ml of DS. The levels of T-cell a dhesion to ECM that were induced by the tested DS molecules resembled those induced by the prototypic chemokine, macrophage inflammatory protein 1 bet a (MIP-1 beta). However, the kinetics of DS-induced T-cell adhesion to FN r esembled that induced by phorbol myristate acetate (PMA), but not that indu ced by MIP-1 beta. This adhesion appeared to involve pr integrin recognitio n and activation, and was associated with specific intracellular activation pathways. Although a first exposure of T cells to certain DS molecules app eared to result in cell adhesion, a subsequent exposure of T cells to pro-a dhesive chemokines, such as MIP-1 beta or RANTES, but not to other pro-adhe sive stimuli, for example interleukin-2 or CD3 cross-linking, resulted in i nhibition of T-cell adhesion to and chemotactic migration through FN. Hence , we propose that the breakdown products of tissues generated by inflammato ry enzymes are part of an intrinsic functional programme, and not necessari ly molecular waste. Moreover, because the DS molecules exert their modulato ry functions within a limited time, it appears that the historical encounte rs of the tissue-invading cells with the constituents of inflamed loci may dictate the cells' behaviour upon subsequent exposure to proinflammatory me diators.