Roles of adhesion molecules in T-cell recognition: fundamental similarities between four integrins on resting human T cells (LFA-1, VLA-4, VLA-5, VLA-6) in expression, binding, and costimulation.

This review summarizes our recent work on expression and function of 4 integrins on resting human CD4+ T cells. Three themes are highlighted: multiplicity of molecular pathways of adhesion, regulation of adhesion, and costimulation by adhesion molecules. Four distinct receptor/ligand interactions have been elucidated: LFA-1/ICAM-1, VLA-5/fibronection, VLA-4/fibronectin, and VLA-6/laminin. Our studies indicate fundamental similarities in function and regulation of these four receptor/ligand interactions: 1) acute activation of the T cell (by CD3/TCR crosslinking or by PMA) induces rapid but transient integrin binding function; and 2) higher expression of each integrin on memory T cells compared to naive T cells results in greater binding of memory cells to each ligand. The identification of T-cell integrins (VLA-4, VLA-5, VLA-6) which interact with ECM components directs attention to the potential importance of T-cell interactions with ECM components which either may be immobilized in ECM or which may act as molecular bridges between cells. The existence of multiple adhesion pathways, of multiple ligands for a single receptor (such as LFA-1/ICAM-1 and LFA-1/ICAM-2), multiple receptors for a single ligand (such as VLA-4/FN and VLA-5/FN), and regulation of ligand expression (ICAM-1) provides opportunities for co-operativity, rebundancy and diversity which the T cell utilizes to exquisitely regulate its adhesive interactions. The thesis that adhesion molecules can be multifunctional receptors that also influence signalling is demonstrated by our findings that each of these integrin receptor/ligand interactions is capable of providing a potent costimulatory signal to CD3-mediated T-cell activation. The importance of interactions of T-cell integrins with their cell surface and ECM ligands is discussed with respect to T-cell migration, differentiation and recognition. Analysis of the precise mechanisms by which T cells regulate and exploit these multiple receptor/ligand interactions and the resulting functional consequences of those interactions will be exciting areas of future research.