Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

NK cell development in bone marrow and liver: site matters

Abstract

The NKp46 protein is found on resting and activated natural killer (NK) cells and is involved in the recognition of malignant and infected cells. The expression of NKp46 is believed to precede that of DX5 in early NK cell development. We show that this is not the case in the bone marrow (BM). Here, NKp46 is predominantly expressed after DX5, whereas the liver harbors a subpopulation that expresses NKp46 but not DX5. NK cell precursors in the liver show much lower levels of Eomesodermin than NK cell precursors in the BM, although they express higher levels of granzymes and unlike the NK cell precursors in the BM are fully able to degranulate and produce interferon gamma (IFN-γ). The development of NK cells thus differs between the two organs. This needs to be considered when using NKp46 and DX5 as NK cell markers and when performing NK cell-specific gene deletion in Ncr1 transgenic mice.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2

References

  1. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat Rev Immunol 2013; 13: 145–149.

    CAS  Article  Google Scholar 

  2. Huntington ND, Nutt SL, Carotta S . Regulation of murine natural killer cell commitment. Front Immunol 2013; 4: 14.

    Article  Google Scholar 

  3. Carotta S, Pang SHM, Nutt SL, Belz GT . Identification of the earliest NK-cell precursor in the mouse BM. Blood 2011; 117: 5449–5452.

    CAS  Article  Google Scholar 

  4. Kim S, Iizuka K, Kang H-SPS, Dokun A, French AR, Greco S et al. In vivo developmental stages in murine natural killer cell maturation. Nat Immunol 2002; 3: 523–528.

    Article  Google Scholar 

  5. Walzer T, Bléry M, Chaix J, Fuseri N, Chasson L, Robbins SH et al. Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46. Proc Natl Acad Sci USA 2007; 104: 3384–3389.

    CAS  Article  Google Scholar 

  6. Narni-Mancinelli E, Chaix J, Fenis A, Kerdiles YM, Yessaad N, Reynders A et al. Fate mapping analysis of lymphoid cells expressing the NKp46 cell surface receptor. Proc Natl Acad Sci USA 2011; 108: 18324–18329.

    CAS  Article  Google Scholar 

  7. Huntington ND, Tabarias H, Fairfax K, Brady J, Hayakawa Y, Degli-Esposti MA et al. NK cell maturation and peripheral homeostasis is associated with KLRG1 up-regulation. J Immunol 2007; 178: 4764–4770.

    CAS  Article  Google Scholar 

  8. Hayakawa Y, Huntington ND, Nutt SL, Smyth MJ . Functional subsets of mouse natural killer cells. Immunol Rev 2006; 214: 47–55.

    CAS  Article  Google Scholar 

  9. Gordon SM, Chaix J, Rupp LJ, Wu J, Madera S, Sun JC et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 2012; 36: 55–67.

    CAS  Article  Google Scholar 

  10. Takeda K, Cretney E, Hayakawa Y, Ota T, Akiba H, Ogasawara K et al. TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. Blood 2005; 105: 2082–2089.

    CAS  Article  Google Scholar 

  11. Seillet C, Huntington ND, Gangatirkar P, Axelsson E, Minnich M, Brady HJM et al. Differential Requirement for Nfil3 during NK Cell Development. J Immunol 2014; 192: 2667–2676.

    CAS  Article  Google Scholar 

  12. Peng H, Jiang X, Chen Y, Sojka DK, Wei H, Gao X et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest 2013; 123: 1444–1456.

    CAS  Article  Google Scholar 

  13. Narni-Mancinelli E, Vivier E . NK cell genesis: a trick of the trail. Immunity 2012; 36: 1–3.

    CAS  Article  Google Scholar 

  14. Daussy C, Faure F, Mayol K, Viel S, Gasteiger G, Charrier E et al. T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J Exp Med 2014; 211: 563–577.

    CAS  Article  Google Scholar 

  15. Vermijlen D, Luo D, Froelich CJ, Medema JP, Kummer JA, Willems E et al. Hepatic natural killer cells exclusively kill splenic/blood natural killer-resistant tumor cells by the perforin/granzyme pathway. J Leukoc Biol 2002; 72: 668–676.

    CAS  PubMed  Google Scholar 

  16. Eckelhart E, Warsch W, Zebedin E, Simma O, Stoiber D, Kolbe T et al. A novel Ncr1-Cre mouse reveals the essential role of STAT5 for NK cell survival and development. Blood 2011; 117: 1565–1573.

    CAS  Article  Google Scholar 

  17. Luche H, Weber O, Nageswara Rao T, Blum C, Fehling HJ . Faithful activation of an extra-bright red fluorescent protein in “knock-in” Cre-reporter mice ideally suited for lineage tracing studies. Eur J Immunol 2007; 37: 43–53.

    CAS  Article  Google Scholar 

  18. Hayakawa Y, Andrews DM, Smyth MJ . Subset analysis of human and mouse mature NK cells. Methods Mol Biol 2010; 612: 27–38.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank P Kudweis and E Straka for their help and HJ Fehling for providing the Rosa-tdRFP mice. The work was supported by the FWF grant SFB F28 (VS, http://www.fwf.ac.at/en/projects/sfb.html).

Author Contributions

DG, EMP, MP-M, CS and AG performed the research and analyzed data; OM and VS provided reagents and/or analytic tools and analyzed data; DG, EMP, SC and VS designed the research and wrote the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to V Sexl or E M Putz.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gotthardt, D., Prchal-Murphy, M., Seillet, C. et al. NK cell development in bone marrow and liver: site matters. Genes Immun 15, 584–587 (2014). https://doi.org/10.1038/gene.2014.55

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2014.55

Further reading

Search

Quick links