title: Transendothelial migratory pathways of V delta 1+TCR gamma delta+ and V delta 2+TCR gamma delta+ T lymphocytes from healthy donors and multiple sclerosis patients: involvement of phosphatidylinositol 3 kinase and calcium calmodulin-dependent kinase II.
abstract: We have previously reported that the Vdelta2(+)TCRgammadelta(+) T lymphocyte subset, expressing the NK receptor protein 1a (NKRP1a; CD161), is expanded in patients with relapsing-remitting multiple sclerosis and uses this molecule to migrate through endothelium. In this work, we show that Vdelta1(+) and Vdelta2(+) gammadelta T lymphocytes use distinct signal transduction pathways to accomplish this function. Indeed, we have found that Vdelta1(+) cells lack NKRP1a and selectively express the platelet endothelial cell adhesion molecule 1 (PECAM1; CD31), which drives transendothelial migration of this cell subset, at variance with Vdelta2(+) T cells, which are PECAM1 negative and use NKRP1a for transmigration. Interestingly, when Vdelta2(+) T cells were pretreated with two specific inhibitors of the calcium calmodulin-dependent kinase II KN62 and KN93, but not with the inactive compound KN92, the number of migrating cells and the rate of transmigration were significantly decreased. In turn, the phosphatidylinositol 3 kinase blockers wortmannin and LY294002 exerted a dose-dependent inhibition of Vdelta1(+) cell migration. Finally, NKRP1a and PECAM1 engagement led to activation of different signal transduction pathways: indeed, oligomerization of NKRP1a on Vdelta2(+) T cells activates calcium calmodulin-dependent kinase II, while occupancy of PECAM1 on Vdelta1(+) cells triggers the phosphatidylinositol 3 kinase-dependent Akt/protein kinase Balpha activation. These findings suggest that subsets of gammadelta T lymphocytes may migrate to the site of lesion in multiple sclerosis using two different signaling pathways to extravasate.
authors.affiliation: Laboratory of Immunology, National Institute for Cancer Research, Genoa, Italy. poggi@vega.cba.unige.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Zocchi
authors.forename: Roberta
authors.initials: R
authors.lastname: Carosio
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferrero
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Angelini
authors.forename: Simona
authors.initials: S
authors.lastname: Galgani
authors.forename: Maria D
authors.initials: MD
authors.lastname: Caramia
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Borsellino
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
mesh_terms: D000954:Antigens, Surface / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000276:immunology*; D002999:Clone Cells; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type; D009103:Multiple Sclerosis / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D055651:NK Cell Lectin-Like Receptor Subfamily B; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis* / Q000097:blood; D011971:Receptors, Immunologic / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000473:pathology
chemical_list: D000954:Antigens, Surface; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D019869:Phosphatidylinositol 3-Kinases; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011971:Receptors, Immunologic; C527203:KLRB1 protein, human; C494918:AKT1 protein, human