PIP5 Kinases Regulate Membrane Phosphoinositide and Actin Composition for Targeted Granule Secretion by Cytotoxic Lymphocytes.

Authors
Gawden-Bone, Christian M 
Frazer, Gordon L 
Richard, Arianne C 
Ma, Claire Y 
Strege, Katharina 

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Type
Article
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Abstract

How cytotoxic T lymphocytes (CTLs) sense T cell receptor (TCR) signaling in order to specialize an area of plasma membrane for granule secretion is not understood. Here, we demonstrate that immune synapse formation led to rapid localized changes in the phosphoinositide composition of the plasma membrane, both reducing phosphoinositide-4-phosphate (PI(4)P), PI(4,5)P2, and PI(3,4,5)P3 and increasing diacylglycerol (DAG) and PI(3,4)P2 within the first 2 min of synapse formation. These changes reduced negative charge across the synapse, triggering the release of electrostatically bound PIP5 kinases that are required to replenish PI(4,5)P2. As PI(4,5)P2 decreased, actin was depleted from the membrane, allowing secretion. Forced localization of PIP5Kβ across the synapse prevented actin depletion, blocking both centrosome docking and secretion. Thus, PIP5Ks act as molecular sensors of TCR activation, controlling actin recruitment across the synapse, ensuring exquisite co-ordination between TCR signaling and CTL secretion.

Publication Date
2018-09-18
Online Publication Date
2018-09-11
Acceptance Date
2018-08-21
Keywords
CTLs, PI(4,5)P2, PIP5K, cytotoxic T lymphocytes, immunological synapse, phosphatidylinositol 4-phosphate 5-kinase, phosphoinositides phosphatidylinositol 4,5-biphosphate, phospholipids, primary cilia, secretion, Actins, Animals, Cell Degranulation, Cell Line, Cell Membrane, Cytoplasmic Granules, Cytotoxicity, Immunologic, Immunological Synapses, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phosphatidylinositols, Phosphotransferases (Alcohol Group Acceptor), Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Cytotoxic
Journal Title
Immunity
Journal ISSN
1074-7613
1097-4180
Volume Title
49
Publisher
Elsevier BV
Sponsorship
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (103930/Z/14/Z)
Medical Research Council (MR/P014178/1)
Addenbrooke's Charitable Trust (ACT) (Minute 23/17 A (ii))
Wellcome Trust (075880/Z/04/A)
Wellcome Trust