PIPKIγ90 Negatively Regulates LFA-1–Mediated Adhesion and Activation in Antigen-Induced CD4+ T Cells

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  • Sarah A Wernimont
    Program in Cellular and Molecular Biology, University of Wisconsin , Madison WI 53706
  • Kyle R Legate
    Department of Molecular Medicine, Max Planck Institute of Biochemistry , Martinsried ,
  • William T N Simonson
    Program in Cellular and Molecular Biology, University of Wisconsin , Madison WI 53706
  • Reinhard Fassler
    Department of Molecular Medicine, Max Planck Institute of Biochemistry , Martinsried ,
  • Anna Huttenlocher
    Department of Pediatrics, University of Wisconsin , Madison WI 53706

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<jats:title>Abstract</jats:title> <jats:p>T cell activation requires the formation and maintenance of stable interactions between T cells and APCs. The formation of stable T cell–APC contacts depends on the activation of the integrin LFA-1 (CD11aCD18). Several positive regulators of LFA-1 activation downstream of proximal TCR signaling have been identified, including talin; however, negative regulators of LFA-1 activity remain largely unexplored. Extended isoform of phosphatidylinositol phosphate kinase type I γ (PIPKIγ90) is a member of the type I phosphatidylinositol phosphate kinase family that has been shown previously to modulate talin activation of integrins through production of phosphatidylinositol 4,5-bisphosphate and direct binding to talin. In this study, we show that PIPKIγ90 negatively regulates LFA-1–mediated adhesion and activation of T cells. Using CD4+ T cells from PIPKIγ90-deficient mice, we show that CD4+ T cells exhibit increased LFA-1-dependent adhesion to ICAM-1 and increased rates of T cell–APC conjugate formation with enhanced LFA-1 polarization at the synapse. In addition to increased adhesiveness, PIPKIγ90-deficient T cells exhibit increased proliferation both in vitro and in vivo and increased production of IFN-γ and IL-2. Together, these results demonstrate that PIPKIγ90 is a negative regulator of Ag-induced T cell adhesion and activation.</jats:p>

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