Transendothelial Migratory Pathways of Vδ1+TCRγδ+ and Vδ2+TCRγδ+ T Lymphocytes from Healthy Donors and Multiple Sclerosis Patients: Involvement of Phosphatidylinositol 3 Kinase and Calcium Calmodulin-Dependent Kinase II

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Abstract
We have previously reported that the Vδ2+TCRγδ+ 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 Vδ1+ and Vδ2+ γδ T lymphocytes use distinct signal transduction pathways to accomplish this function. Indeed, we have found that Vδ1+ 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 Vδ2+ T cells, which are PECAM1 negative and use NKRP1a for transmigration. Interestingly, when Vδ2+ 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 Vδ1+ cell migration. Finally, NKRP1a and PECAM1 engagement led to activation of different signal transduction pathways: indeed, oligomerization of NKRP1a on Vδ2+ T cells activates calcium calmodulin-dependent kinase II, while occupancy of PECAM1 on Vδ1+ cells triggers the phosphatidylinositol 3 kinase-dependent Akt/protein kinase Bα activation. These findings suggest that subsets of γδ T lymphocytes may migrate to the site of lesion in multiple sclerosis using two different signaling pathways to extravasate.