Regulation of conformer-specific activation of the integrin LFA-1 by a chemokine-triggered Rho signaling module.
Regulation of the affinity of the beta(2) integrin LFA-1 by chemokines is critical to lymphocyte trafficking, but the signaling mechanisms that control this process are not well understood. Here we investigated the signaling events controlling LFA-1 affinity triggering by chemokines in human primary T lymphocytes. We found that the small GTPase Rac1 mediated chemokine-induced LFA-1 affinity triggering and lymphocyte arrest in high endothelial venules. Unexpectedly, another Rho family member, Cdc42, negatively regulated LFA-1 activation. The Rho effectors PLD1 and PIP5KC were also critical to LFA-1 affinity modulation. Notably, PIP5KC was found to specifically control the transition of LFA-1 from an extended low-intermediate state to a high-affinity state, which correlated with lymphocyte arrest. Thus, chemokines control lymphocyte trafficking by triggering a Rho-dependent signaling cascade leading to conformer-specific modulation of LFA-1 affinity.
Bolomini-Vittori
Matteo
M
University of Verona, School of Medicine, Department of Pathology, Division of General Pathology, Verona 37134, Italy.
Montresor
Alessio
A
Giagulli
Cinzia
C
Staunton
Donald
D
Rossi
Barbara
B
Martinello
Marianna
M
Constantin
Gabriela
G
Laudanna
Carlo
C
D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology*; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000276:immunology / Q000378:metabolism*
D018925:Chemokines; D016169:Lymphocyte Function-Associated Antigen-1; D034741:RNA, Small Interfering; D054460:rho-Associated Kinases