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PIPKI gamma 90 negatively regulates LFA-1-mediated adhesion and activation in antigen-induced CD4+ T cells.

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.

Pubmed ID: 20855869

Authors

  • Wernimont SA
  • Legate KR
  • Simonson WT
  • Fassler R
  • Huttenlocher A

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Data

October 15, 2010

Associated Grants

  • Agency: NIAID NIH HHS, Id: R01 AI068062
  • Agency: NCI NIH HHS, Id: R01 CA085862
  • Agency: NCI NIH HHS, Id: R01 CA085862

Mesh Terms

  • Animals
  • Antigen-Presenting Cells
  • CD4-Positive T-Lymphocytes
  • Cell Adhesion
  • Cell Proliferation
  • Cell Separation
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Immunoblotting
  • Intercellular Adhesion Molecule-1
  • Lymphocyte Activation
  • Lymphocyte Function-Associated Antigen-1
  • Mice
  • Mice, Knockout
  • Phosphotransferases (Alcohol Group Acceptor)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transduction, Genetic