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.
Wernimont
Sarah A
SA
Program in Cellular and Molecular Biology, University of Wisconsin, Madison WI 53706, USA.
Legate
Kyle R
KR
Simonson
William T N
WT
Fassler
Reinhard
R
Huttenlocher
Anna
A
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion; D049109:Cell Proliferation; D002469:Cell Separation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic
D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase