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However, the signaling pathway linking iTCR and PLZF remains unclear. Here, we report that a serine\/threonine kinase, protein kinase D (PKD), plays a pivotal role in iNKT cell development. In T cell\u2013specific PKD-deficient (Prkd2\/3\u2206CD4) mice, PLZF induction and iNKT cell generation were severely impaired, which were rescued by introduction of a PLZF transgene. We identified the transcription factor Ikaros as a substrate of PKD upon iTCR stimulation. Knock-in mice carrying a phosphorylation-defective mutant Ikaros (Ikzf1S267\/275A) exhibited an impairment of iNKT cell development, whereas conventional T cells were normal. In iNKT cells, Ikaros binds to the upstream region of the PLZF gene to induce its transcription. Mutant mice lacking the Ikaros-binding site (Zbtb16\u2206IBS) generated fewer iNKT cells than WT mice. These results suggest that PKD links iTCRs to PLZF induction through Ikaros, thereby mediating iNKT cell development.<\/jats:p>","DOI":"10.1084\/jem.20250541","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T06:20:52Z","timestamp":1755584452000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Invariant TCR-triggered protein kinase D activation mediates NKT cell development"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4922-6751","authenticated-orcid":true,"given":"Eri","family":"Ishikawa","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Institute for Microbial Diseases, The University of Osaka 1 Department of Molecular Immunology, , 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