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Tec Kinases Regulate TCR-Mediated Recruitment of Signaling Molecules and Integrin-Dependent Cell Adhesion¹

Lisa D. Finkelstein^*, Yoji Shimizu and Pamela L. Schwartzberg^2,*

^* National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and Department of Laboratory Medicine and Pathology, Center for Immunology, and Cancer Center University of Minnesota, Minneapolis, MN 55455

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-. 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 C, 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 C, 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.

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