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1+TCR
+ and V2+TCR+ T Lymphocytes from Healthy Donors and Multiple Sclerosis Patients: Involvement of Phosphatidylinositol 3 Kinase and Calcium Calmodulin-Dependent Kinase II1
* Laboratory of Immunology, National Institute for Cancer Research, Genoa, Italy;
Laboratory of Tumor Immunology, Scientific Institute San Raffaele, Milan, Italy;
Laboratory of Neuroimmunology, IRCCS Santa Lucia Foundation,
Department of Neurosciences "Lancisi," Ospedale San Camillo, and
¶ Department of Neurosciences, University of Tor Vergata, Rome, Italy
We have previously reported that the
V
2+TCR
+ 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
V1+ and V2+ T lymphocytes use
distinct signal transduction pathways to accomplish this function.
Indeed, we have found that V1+ 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 V2+ T cells, which are PECAM1
negative and use NKRP1a for transmigration. Interestingly, when
V2+ 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 V1+ cell migration.
Finally, NKRP1a and PECAM1 engagement led to activation of different
signal transduction pathways: indeed, oligomerization of NKRP1a on
V2+ T cells activates calcium calmodulin-dependent
kinase II, while occupancy of PECAM1 on V1+ cells
triggers the phosphatidylinositol 3 kinase-dependent Akt/protein kinase
B
activation. These findings suggest that subsets of T
lymphocytes may migrate to the site of lesion in multiple sclerosis
using two different signaling pathways to
extravasate.
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