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

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 CD3ζ, ZAP-70, and Lck. Silencing INPP5E in T-cells impaired polarized distribution of CD3ζ 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 CD3ζ 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.