Migratory pathways of gammadelta T cells and response to CXCR3 and CXCR4 ligands: adhesion molecules involved and implications for multiple sclerosis pathogenesis.
Gammadelta T lymphocytes are thought to be involved in multiple sclerosis (MS) pathogenesis. In this work, we discuss the characteristics of these cells and possible implications in the pathogenesis of MS, focusing on the mechanism(s) underlying extravasation and tissue localization. Phenotype and transendothelial migration of gammadelta T cells from healthy donors and patients with relapsing-remitting MS were studied. In MS patients the V delta 2 T cell subset, expressing NKRP1A/CD161 adhesion molecule, is expanded and capable of transendothelial migration. V delta 1/V delta 2 subsets use distinct signal transduction pathways: V delta 1 cells lack NKRP1A and express PECAM-1/CD31, which drives transmigration, while V delta 2 cells are PECAM-1 negative and use NKRP1A. V delta 2 migration is coupled with CAMKII, whereas V delta 1 depend on PI-3K. NKRP1A and PECAM-1 selectively activate the two pathways: indeed, oligomerization of NKRP1A on V delta 2 T cells leads to CAMKII activation, occupancy of PECAM-1 on V delta 1 cells triggers the PI-3K-dependent Akt/PKB pathway. Moreover, V delta 2 T cells are CXCR3(bright)CXCR4(dull), while V delta 1 are mostly CXCR4(+). V delta 1 and V delta 2 cells transmigrate in response to IP-10/CXCL10 and SDF-1/CXCL12 according to the expression of their specific receptors. In a fraction of V delta 1 T cells coexpressing CXCR3 and CXCR4, the homeostatic chemokine 6Ckine/SLC/CCL21 is more effective. IP-10/CXCL10 or 6Ckine/SLC/CCL21 and SDF-1/CXCL12-induced transmigration is coupled to PI-3K/Akt/PKB, but only CXCR3 is capable of inducing CAMKII activation. We suggest that both subsets of gammadelta T lymphocytes may migrate to the site of lesion in MS using two different signaling pathways to extravasate and responding to different chemokines.
Poggi
A
A
Laboratory of Experimental Oncology D, National Institute for Cancer Research, Genoa, Italy.
Zancolli
M
M
Catellani
S
S
Borsellino
G
G
Battistini
L
L
Zocchi
M R
MR
D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement; D006801:Humans; D008024:Ligands; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D014774:Virulence