2025年 新着論文 42 細胞情報学分野から論文が発表されました

Invariant TCR-triggered protein kinase D activation mediates NKT cell development

J Exp Med. 2025 Dec 1;222(12):e20250541. doi: 10.1084/jem.20250541. Epub 2025 Sep 18.

Authors

Eri Ishikawa  1   2 Hidetaka Kosako  3 Daisuke Motooka  4 Mai Imasaka  5 Hiroshi Watarai  6 Masaki Ohmuraya  5 Sho Yamasaki  1   2   7   8

Affiliations

  • 1 Department of Molecular Immunology, Research Institute for Microbial Diseases, The University of Osaka, Suita, Japan.
  • 2 Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), The University of Osaka, Suita, Japan.
  • 3 Division of Cell Signaling, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
  • 4 Genome Information Research Center, Research Institute for Microbial Diseases, The University of Osaka , Suita, Japan.
  • 5 Department of Genetics, Hyogo Medical University, Nishinomiya, Japan.
  • 6 Department of Immunology and Stem Cell Biology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
  • 7 Center for Infectious Disease Education and Research (CiDER), The University of Osaka , Suita, Japan.
  • 8 Center for Advanced Modalities and DDS (CAMaD), The University of Osaka , Suita, Japan.

Abstract

Development of invariant natural killer T (iNKT) cells in the thymus requires cell-cell interaction through invariant TCR (iTCR) and CD1d, which induces expression of the transcription factor, promyelocytic leukemia zinc finger (PLZF). 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-specific PKD-deficient (Prkd2/3∆CD4) 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∆IBS) generated fewer iNKT cells than WT mice. These results suggest that PKD links iTCRs to PLZF induction through Ikaros, thereby mediating iNKT cell development.

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