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

Tzu Yuan Chiu, Chien Hui Lo, Yi Hsuan Lin, Yun Di Lai, Shan Shan Lin, Ya Tian Fang, Wei Syun Huang, Shen Yan Huang, Pei Yuan Tsai, Fu Hua Yang, Weng Man Chong, Yi Chieh Wu, Hsing Chen Tsai, Ya Wen Liu, Chia Lin Hsu, Jung Chi Liao*, Won Jing Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The 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.

Original languageEnglish
Article number911
JournalCommunications Biology
Issue number1
StatePublished - Dec 2023


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