Chemokines fail to up-regulate beta 1 integrin-dependent adhesion in human Th2 T lymphocytes

Th1 and Th2 cells are functionally distinct subsets of CD4(+) T lymphocytes whose tissue-specific homing to sites of inflammation is regulated in part by the differential expression of P- and E-selectin ligands and selected chemokine receptors, Here we investigated the expression and function of beta(1) integrins in Th1 and Th2 cells polarized in vitro, Th1 lymphocytes adhere transiently to the extracellular matrix ligands laminin 1 and fibronectin in response to chemokines such as RANTES and stromal cell-derived factor-1, and this process is paralleled by the activation of the Rad GTPase and by a rapid burst of actin polymerization, Selective inhibitors of phosphoinositide-3 kinase prevent efficiently all of the above processes, whereas the protein kinase C inhibitor bisindolylmaleimide prevents chemokine-induced adhesion without affecting Rad activation and actin polymerization, Notably, chemokine-induced adhesion to beta(1) integrin ligands is markedly reduced in Th2 cells. Such a defect cannot be explained by a reduced sensitivity to chemokine stimulation in this T cell subset, nor by a defective activation of the signaling cascade involving phosphoinositide-3 kinase, Rad, and actin turnover, as all these processes are activated at comparable levels by chemokines in the two subsets. We propose that reduced beta(1) integrin-mediated adhesion in Th2 cells may restrain their ability to invade and/or reside in sites of chronic inflammation, which are characterized by thickening of basement membranes and extensive fibrosis, requiring efficient interaction with organized extracellular matrices.