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

J Immunol. 2002 Jun 15;168(12):6071-7. doi: 10.4049/jimmunol.168.12.6071.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Surface / biosynthesis
  • Antigens, Surface / immunology
  • Antigens, Surface / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology*
  • Cell Movement / immunology*
  • Clone Cells
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / immunology*
  • Endothelium, Vascular / pathology
  • Enzyme Activation / immunology
  • Humans
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Lectins, C-Type*
  • Multiple Sclerosis / enzymology
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / metabolism
  • Multiple Sclerosis / pathology
  • NK Cell Lectin-Like Receptor Subfamily B
  • Phosphatidylinositol 3-Kinases / physiology*
  • Platelet Endothelial Cell Adhesion Molecule-1 / biosynthesis
  • Platelet Endothelial Cell Adhesion Molecule-1 / physiology
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • Receptors, Antigen, T-Cell, gamma-delta / biosynthesis*
  • Receptors, Antigen, T-Cell, gamma-delta / blood
  • Receptors, Immunologic / biosynthesis
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / enzymology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / pathology

Substances

  • Antigens, Surface
  • KLRB1 protein, human
  • Lectins, C-Type
  • NK Cell Lectin-Like Receptor Subfamily B
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Immunologic
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases