INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control

Author:

Chiu Tzu-YuanORCID,Lo Chien-Hui,Lin Yi-Hsuan,Lai Yun-Di,Lin Shan-Shan,Fang Ya-Tian,Huang Wei-Syun,Huang Shen-Yan,Tsai Pei-Yuan,Yang Fu-Hua,Chong Weng Man,Wu Yi-Chieh,Tsai Hsing-ChenORCID,Liu Ya-WenORCID,Hsu Chia-Lin,Liao Jung-ChiORCID,Wang Won-JingORCID

Abstract

AbstractThe immune synapse, a highly organized structure formed at the interface between T lymphocytes and antigen-presenting cells (APCs), is essential for T cell activation and the adaptive immune response. It has been shown that this interface shares similarities with the primary cilium, a sensory organelle in eukaryotic cells, although the roles of ciliary proteins on the immune synapse remain elusive. Here, we find that inositol polyphosphate-5-phosphatase E (INPP5E), a cilium-enriched protein responsible for regulating phosphoinositide localization, is enriched at the immune synapse in Jurkat T-cells during superantigen-mediated conjugation or antibody-mediated crosslinking of TCR complexes, and forms a complex with CD3ζ, ZAP-70, and Lck. Silencing INPP5E in Jurkat T-cells impairs the polarized distribution of CD3ζ at the immune synapse and correlates with a failure of PI(4,5)P2 clearance at the center of the synapse. Moreover, INPP5E silencing decreases proximal TCR signaling, including phosphorylation of CD3ζ and ZAP-70, and ultimately attenuates IL-2 secretion. Our results suggest that INPP5E is a new player in phosphoinositide manipulation at the synapse, controlling the TCR signaling cascade.

Publisher

Springer Science and Business Media LLC

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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