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Alternative pathway for the development of Vα14+ NKT cells directly from CD4CD8 thymocytes that bypasses the CD4+CD8+ stage

Nature Immunology volume 18, pages 274282 (2017) | Download Citation

Abstract

Although invariant Vα14+ natural killer T cells (NKT cells) are thought to be generated from CD4+CD8+ double-positive (DP) thymocytes, the developmental origin of CD4CD8 double-negative (DN) NKT cells still remains unresolved. Here we provide definitive genetic evidence obtained, through studies of mice with DP-stage-specific ablation of expression of the gene encoding the recombinase component RAG-2 (Rag2) and by a fate-mapping approach, that supports the proposal of the existence of an alternative developmental pathway through which a fraction of DN NKT cells with strong T-helper-type-1 (TH1)-biased and cytotoxic characteristics develop from late DN-stage thymocytes, bypassing the DP stage. These findings provide new insight into understanding of the development of NKT cells and propose a role for timing of expression of the invariant T cell antigen receptor in determining the functional properties of NKT cells.

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Acknowledgements

We thank A. Singer (US National Institutes of Health) for E8III-Cre mice; F. Constantini (Columbia University) for Rosa26-YFP mice; D. Littman (New York University) for Rorc–/– mice; P. Burrows for critical reading of this manuscript; T. Hasegawa for support with animal facility services; and N. Takeuchi for secretarial assistance. Supported by the Japan Society for the Promotion of Science (KAKENHI grants 24790490 to N.D. and 23229005 to M.T.).

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Affiliations

  1. Laboratory for Immune Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Nyambayar Dashtsoodol
    • , Tomokuni Shigeura
    • , Minako Aihara
    • , Ritsuko Ozawa
    • , Satoshi Kojo
    • , Michishige Harada
    •  & Masaru Taniguchi
  2. Core Research Laboratory, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia.

    • Nyambayar Dashtsoodol
  3. Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Takaho A Endo
    • , Takashi Watanabe
    •  & Osamu Ohara

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Contributions

N.D. conceived of the study, performed experiments, analyzed data and wrote the paper; T.S., M.A. and R.O. assisted with experiments; S.K. and M.H. discussed experiments; T.A.E. did bioinformatics analyses; T.W. and O.O. performed next-generation sequencing experiments; M.T. directed the study and wrote the paper.

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The authors declare no competing financial interests.

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Correspondence to Nyambayar Dashtsoodol or Masaru Taniguchi.

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https://doi.org/10.1038/ni.3668

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