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 Rac1 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 Rac1 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, Rac1, 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.
Clissi
B
B
Department of Molecular Pathology and Medicine, Human Immunology Unit, Scientific Institute San Raffaele-DIBIT, Milan, Italy.
D'Ambrosio
D
D
Geginat
J
J
Colantonio
L
L
Morrot
A
A
Freshney
N W
NW
Downward
J
J
Sinigaglia
F
F
Pardi
R
R
D000199:Actins / Q000378:metabolism; D001704:Biopolymers / Q000378:metabolism; D018821:CD18 Antigens / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D018946:Chemokine CCL5 / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039121:Integrin alpha6beta1; D019012:Integrin beta1 / Q000096:biosynthesis / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017474:Receptors, Laminin / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*
D000199:Actins; D001704:Biopolymers; D018821:CD18 Antigens; C515255:CXCL12 protein, human; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D039121:Integrin alpha6beta1; D019012:Integrin beta1; D016023:Integrins; D007797:Laminin; D017474:Receptors, Laminin; D002118:Calcium