Phosphatidylinositol (4,5) bisphosphate controls T cell activation by regulating T cell rigidity and organization

Yi Sun, Radhika D. Dandekar, Yuntao S. Mao, Helen L. Yin, Christoph Wülfing

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Article numbere27227
JournalPloS one
Volume6
Issue number11
DOIs
StatePublished - Nov 11 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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