title: Phosphatidylinositol (4,5) bisphosphate controls T cell activation by regulating T cell rigidity and organization.
abstract: Here we investigate the role of Phosphatidylinositol (4,5) bisphosphate (PIP(2)) in the physiological activation of primary murine T cells by antigen presenting cells (APC) by addressing two principal challenges in PIP(2) biology. First, PIP(2) is a regulator of cytoskeletal dynamics and a substrate for second messenger generation. The relative importance of these two processes needs to be determined. Second, PIP(2) is turned over by multiple biosynthetic and metabolizing enzymes. The joint effect of these enzymes on PIP(2) distributions needs to be determined with resolution in time and space. We found that T cells express four isoforms of the principal PIP(2)-generating enzyme phosphatidylinositol 4-phosphate 5-kinase (PIP5K) with distinct spatial and temporal characteristics. In the context of a larger systems analysis of T cell signaling, these data identify the T cell/APC interface and the T cell distal pole as sites of differential PIP(2) turnover. Overexpression of different PIP5K isoforms, as corroborated by knock down and PIP(2) blockade, yielded an increase in PIP(2) levels combined with isoform-specific changes in the spatiotemporal distributions of accessible PIP(2). It rigidified the T cell, likely by impairing the inactivation of Ezrin Moesin Radixin, delayed and diminished the clustering of the T cell receptor at the cellular interface, reduced the efficiency of T cell proximal signaling and IL-2 secretion. These effects were consistently more severe for distal PIP5K isoforms. Thus spatially constrained cytoskeletal roles of PIP(2) in the control of T cell rigidity and spatiotemporal organization dominate the effects of PIP(2) on T cell activation.
authors.affiliation: Department of Immunology, UT Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Radhika D
authors.initials: RD
authors.lastname: Dandekar
authors.forename: Yuntao S
authors.initials: YS
authors.lastname: Mao
authors.forename: Helen L
authors.initials: HL
authors.lastname: Yin
authors.forename: Christoph
authors.initials: C
authors.lastname: Wülfing
mesh_terms: D000199:Actins; D000818:Animals; D002478:Cells, Cultured; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D000199:Actins; D007376:Interleukin-2; D019269:Phosphatidylinositol 4,5-Diphosphate; D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase
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