Tec kinases regulate TCR-mediated recruitment of signaling molecules and integrin-dependent cell adhesion.
T cells deficient in the Tec kinases Itk or Itk and Rlk exhibit defective TCR-stimulated proliferation, IL-2 production, and activation of phospholipase C-gamma. Evidence also implicates Tec kinases in actin cytoskeleton regulation, which is necessary for cell adhesion and formation of the immune synapse in T lymphocytes. In this study we show that Tec kinases are required for TCR-mediated up-regulation of adhesion via the LFA-1 integrin. We also demonstrate that the defect in adhesion is associated with defective clustering of LFA-1 and talin at the site of interaction of Rlk-/-Itk-/- and Itk-/- T cells with anti-TCR-coated beads. Defective recruitment of Vav1, protein kinase Ctheta, and Pyk2 was also observed in Rlk-/-Itk-/- and Itk-/- T cells. Stimulation with ICAM-2 in conjunction with anti-TCR-coated beads enhanced polarization of Vav1, protein kinase Ctheta, and Pyk2 in wild-type cells, demonstrating a role for integrins in potentiating the recruitment of signaling molecules in T cells. Increased recruitment of signaling molecules was most pronounced under conditions of low TCR stimulation. Under these suboptimal TCR stimulation conditions, ICAM-2 could also enhance the recruitment of signaling molecules in Itk-/-, but not Rlk-/-Itk-/- T cells. Thus, Tec kinases play key roles in regulating TCR-mediated polarization of integrins and signaling molecules to the site of TCR stimulation as well as the up-regulation of integrin adhesion.
Finkelstein
Lisa D
LD
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Shimizu
Yoji
Y
Schwartzberg
Pamela L
PL
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000502:physiology; D016023:Integrins / Q000502:physiology*; D007527:Isoenzymes / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D000074121:Protein Kinase C-theta; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; C480027:ICAM-2 protein, mouse; D016023:Integrins; D007527:Isoenzymes; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta