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bioRxiv · 10.1101/2021.01.06.425541

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

Chiu, T.-Y.·Yang, F.-H.·Chong, W. M.·Tsai, H.-C.·Wang, W.-J.·Liao, J.-C.
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Abstract

The immune synapse, a specialized interface formed between T lymphocytes and antigen-presenting cells (APCs) after antigen recognition, 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 roles of ciliary proteins on the immune synapse remain elusive. In this study, we find that inositol polyphosphate-5-phosphatase E (INPP5E), a cilium-enriched protein responsible for regulating phosphoinositide localization, accumulated at the immune synapse during antigen-specific conjugation or antibody capping, and formed a complex with CD3{zeta}, ZAP-70, and Lck. Silencing INPP5E in T-cells impaired polarized distribution of CD3{zeta} at the immune synapse, and correlated with a failure of PI(4,5)P2 clearance at the center of the synapse. Moreover, INPP5E silencing decreased proximal TCR signaling, including phosphorylation of CD3{zeta} and ZAP-70, and finally, attenuated IL-2 secretion. Our results suggest that INPP5E is a new player in phosphoinositide manipulation at the synapse, controlling the TCR signaling cascade.

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Chiu, T.-Y., Yang, F.-H., Chong, W. M., Tsai, H.-C., Wang, W.-J., Liao, J.-C.. 2021-01-07. INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control. https://doi.org/10.1101/2021.01.06.425541

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