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Themis2 regulates natural killer cell memory function and formation

Author

Listed:
  • Tsukasa Nabekura

    (University of Tsukuba
    University of Tsukuba
    University of Tsukuba)

  • Elfira Amalia Deborah

    (University of Tsukuba
    University of Tsukuba)

  • Saeko Tahara

    (University of Tsukuba
    University of Tsukuba
    University of Tsukuba)

  • Yuya Arai

    (University of Tsukuba
    University of Tsukuba
    University of Tsukuba)

  • Paul E. Love

    (National Institutes of Health)

  • Koichiro Kako

    (University of Tsukuba
    University of Tsukuba)

  • Akiyoshi Fukamizu

    (University of Tsukuba)

  • Masafumi Muratani

    (University of Tsukuba)

  • Akira Shibuya

    (University of Tsukuba
    University of Tsukuba
    University of Tsukuba)

Abstract

Immunological memory is a hallmark of the adaptive immune system. Although natural killer (NK) cells are innate immune cells important for the immediate host defence, they can differentiate into memory NK cells. The molecular mechanisms controlling this differentiation are yet to be fully elucidated. Here we identify the scaffold protein Themis2 as a critical regulator of memory NK cell differentiation and function. Themis2-deficient NK cells expressing Ly49H, an activating NK receptor for the mouse cytomegalovirus (MCMV) antigen m157, show enhanced differentiation into memory NK cells and augment host protection against MCMV infection. Themis2 inhibits the effector function of NK cells after stimulation of Ly49H and multiple activating NK receptors, though not specific to memory NK cells. Mechanistically, Themis2 suppresses Ly49H signalling by attenuating ZAP70/Syk phosphorylation, and it also translocates to the nucleus, where it promotes Zfp740-mediated repression to regulate the persistence of memory NK cells. Zfp740 deficiency increases the number of memory NK cells and enhances the effector function of memory NK cells, which further supports the relevance of the Themis2-Zfp740 pathway. In conclusion, our study shows that Themis2 quantitatively and qualitatively regulates NK cell memory formation.

Suggested Citation

  • Tsukasa Nabekura & Elfira Amalia Deborah & Saeko Tahara & Yuya Arai & Paul E. Love & Koichiro Kako & Akiyoshi Fukamizu & Masafumi Muratani & Akira Shibuya, 2023. "Themis2 regulates natural killer cell memory function and formation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42578-8
    DOI: 10.1038/s41467-023-42578-8
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    References listed on IDEAS

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    1. Lewis L. Lanier & Brian C. Corliss & Jun Wu & Clement Leong & Joseph H. Phillips, 1998. "Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells," Nature, Nature, vol. 391(6668), pages 703-707, February.
    2. Joseph C. Sun & Joshua N. Beilke & Lewis L. Lanier, 2009. "Erratum: Adaptive immune features of natural killer cells," Nature, Nature, vol. 457(7233), pages 1168-1168, February.
    3. Qi Cao & Xiaoju Wang & Meng Zhao & Rendong Yang & Rohit Malik & Yuanyuan Qiao & Anton Poliakov & Anastasia K. Yocum & Yong Li & Wei Chen & Xuhong Cao & Xia Jiang & Arun Dahiya & Clair Harris & Felix Y, 2014. "The central role of EED in the orchestration of polycomb group complexes," Nature Communications, Nature, vol. 5(1), pages 1-13, May.
    4. Joseph C. Sun & Joshua N. Beilke & Lewis L. Lanier, 2009. "Adaptive immune features of natural killer cells," Nature, Nature, vol. 457(7229), pages 557-561, January.
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