Distinct divalent cation requirements for integrin-mediated CD4⁺ T lymphocyte adhesion to ICAM-1, fibronectin, VCAM-1, and invasin

Integrins are a large family of cell surface receptors that mediate the adhesion of cells to other cells and to components of the extracellular matrix. Various divalent cations, particularly Ca²⁺ and Mn²⁺, have been shown to modulate the functional activity of many different integrins expressed on a wide variety of cell types. In this study, we have characterized the divalent cation requirements for the adhesion of human peripheral CD4⁺ T cells to four distinct integrin ligands: the α4β1 and α5β1 ligand fibronectin, the α4β1 ligand VCAM-1, the LFA-1 ligand ICAM- 1, and the α4β1 bacterial ligand invasin. We find that there are distinct divalent cation requirements for T cell adhesion to each of these ligands: 1) Mg²⁺/EGTA treatment selectively up-regulates T cell adhesion to ICAM-1; 2) Mn²⁺ coordinately up-regulates adhesion to ICAM-1, fibronectin, and VCAM- 1, with a peak response at 100 μM Mn²⁺; 3) Ca²⁺ can selectively support adhesion to VCAM-1 induced by activation and inhibit Mn²⁺-dependent adhesion to ICAM-1; and 4) binding to invasin is maximal in the presence of Ca²⁺, Mg²⁺, or Mn²⁺. Furthermore, divalent cation modifications do not fully up-regulate T cell adhesion to fibronectin, VCAM-1, and ICAM-1, because additional cell activation with phorbol ester treatment can further enhance adhesion in the presence of Mn²⁺. These results suggest that modification of divalent cations may provide a mechanism by which an individual integrin receptor/ligand interaction can be specifically and selectively regulated.