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.

A point mutation in the linker domain of mouse STAT5A is associated with impaired NK-cell regulation

Genes & Immunity volume 21, pages 136–141 (2020)Cite this article

Subjects

Abstract

The transcription factor STAT5 is critical for peripheral NK-cell survival, proliferation, and cytotoxic function. STAT5 refers to two highly related proteins, STAT5A and STAT5B. In this study, we verified the importance of STAT5A isoform for NK cells. We characterized an incidental chemically induced W484G mutation in the Stat5a gene and found that this mutation was associated with a reduction of STAT5A protein expression. Closer examination of NK-cell subsets from Stat5a mutant mice showed marked reductions in NK-cell number and maturation. IL-15 treatment of Stat5a mutant NK cells exhibited defective induction of both STAT5 and mTOR signaling pathways and reduced expression of granzyme B and IFN-γ. Finally, we observed that Stat5a mutant mice revealed more tumor growth upon injection of RMA-S tumor cell line. Overall, our results demonstrate that the W484G mutation in the linker domain of STAT5A is sufficient to compromise STAT5A function in NK-cell homeostasis, responsiveness, and tumoricidal function.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

References

  1. Paul S, Lal G. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front Immunol. 2017;8:1124.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sojka DK, Plougastel-Douglas B, Yang L, Pak-Wittel MA, Artyomov MN, Ivanova Y, et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife. 2014;3:e01659.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Marcais A, Cherfils-Vicini J, Viant C, Degouve S, Viel S, Fenis A, et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol. 2014;15:749–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lin JX, Du N, Li P, Kazemian M, Gebregiorgis T, Spolski R, et al. Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells. Nat Commun. 2017;8:1320.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Imada K, Bloom ET, Nakajima H, Horvath-Arcidiacono JA, Udy GB, Davey HW, et al. Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. J Exp Med. 1998;188:2067–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Villarino AV, Sciume G, Davis FP, Iwata S, Zitti B, Robinson GW, et al. Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells. J Exp Med. 2017;214:2999–3014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cook MC, Vinuesa CG, Goodnow CC. ENU-mutagenesis: insight into immune function and pathology. Curr Opin Immunol. 2006;18:627–33.

    Article  CAS  PubMed  Google Scholar 

  8. Kennedy JM, Fodil N, Torre S, Bongfen SE, Olivier JF, Leung V, et al. CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation. J Exp Med. 2014;211:2519–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Torre S, Polyak MJ, Langlais D, Fodil N, Kennedy JM, Radovanovic I, et al. USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation. Nat Immunol. 2017;18:54–63.

    Article  CAS  PubMed  Google Scholar 

  10. Quwailid MM, Hugill A, Dear N, Vizor L, Wells S, Horner E, et al. A gene-driven ENU-based approach to generating an allelic series in any gene. Mamm Genome. 2004;15:585–91.

    Article  CAS  PubMed  Google Scholar 

  11. Caignard G, Eva MM, van Bruggen R, Eveleigh R, Bourque G, Malo D, et al. Mouse ENU mutagenesis to understand immunity to infection: methods, selected examples, and perspectives. Genes. 2014;5:887–925.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Caignard G, Leiva-Torres GA, Leney-Greene M, Charbonneau B, Dumaine A, Fodil-Cornu N, et al. Genome-wide mouse mutagenesis reveals CD45-mediated T cell function as critical in protective immunity to HSV-1. PLoS Pathog. 2013;9:e1003637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fodil N, Langlais D, Moussa P, Boivin GA, Di Pietrantonio T, Radovanovic I, et al. Specific dysregulation of IFNgamma production by natural killer cells confers susceptibility to viral infection. PLoS Pathog. 2014;10:e1004511.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Mancini M, Caignard G, Charbonneau B, Dumaine A, Wu N, Leiva-Torres GA, et al. Rel-dependent immune and central nervous system mechanisms control viral replication and inflammation during mouse herpes simplex encephalitis. J Immunol. 2019;202:1479–93.

    Article  CAS  PubMed  Google Scholar 

  15. Desrosiers MP, Kielczewska A, Loredo-Osti JC, Adam SG, Makrigiannis AP, Lemieux S, et al. Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection. Nat Genet. 2005;37:593–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Karre K, Ljunggren HG, Piontek G, Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986;319:675–8.

    Article  CAS  PubMed  Google Scholar 

  17. Yuki KE, Marei H, Fiskin E, Eva MM, Gopal AA, Schwartzentruber JA, et al. CYRI/FAM49B negatively regulates RAC1-driven cytoskeletal remodelling and protects against bacterial infection. Nat Microbiol. 2019;4:1516–31.

    Article  CAS  PubMed  Google Scholar 

  18. Gotthardt D, Putz EM, Grundschober E, Prchal-Murphy M, Straka E, Kudweis P, et al. STAT5 is a key regulator in NK cells and acts as a molecular switch from tumor surveillance to tumor promotion. Cancer Discov. 2016;6:414–29.

    Article  CAS  PubMed  Google Scholar 

  19. Clinthorne JF, Beli E, Duriancik DM, Gardner EM. NK cell maturation and function in C57BL/6 mice are altered by caloric restriction. J Immunol. 2013;190:712–22.

    Article  CAS  PubMed  Google Scholar 

  20. Kastrukoff LF, Lau AS, Takei F, Carbone FR, Scalzo AAA. NK complex-linked locus restricts the spread of herpes simplex virus type 1 in the brains of C57BL/6 mice. Immunol Cell Biol. 2015;93:877–84.

    Article  CAS  PubMed  Google Scholar 

  21. Brizic I, Lenac Rovis T, Krmpotic A, Jonjic S. MCMV avoidance of recognition and control by NK cells. Semin Immunopathol. 2014;36:641–50.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank P. D’Arcy for her technical assistance on animal husbandry and injection. We are grateful to the following core facilities: the Life Science Complex Cell Vision Core Facility for flow cytometry (Mcgill University) and The Centre for Phenogenomics, Infection and Inflammation Core (Toronto, Canada),

Author information

Authors and Affiliations

  1. Department of Human Genetics, McGill University, Montreal, QC, H3A 0C7, Canada

    Salma Chehboun, Gabriel André Leiva-Torres, Benoît Charbonneau & Silvia Marina Vidal

  2. McGill Research Centre on Complex Traits, McGill University, Montreal, QC, H3G 0B1, Canada

    Salma Chehboun, Gabriel André Leiva-Torres, Benoît Charbonneau & Silvia Marina Vidal

  3. McGill University and Genome Québec Innovation Centre, Montreal, QC, H3A 0G1, Canada

    Robert Eveleigh & Guillaume Bourque

Authors
  1. Salma Chehboun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriel André Leiva-Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Benoît Charbonneau
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Eveleigh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guillaume Bourque
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Silvia Marina Vidal
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SC and GALT performed the experiments. SC, GALT, and SMV designed and analyzed the experiments. BC assisted with animal experiments. RE and GB performed the initial exome sequencing. SC and SMV wrote the manuscript. All authors reviewed and edited the manuscript.

Corresponding author

Correspondence to Silvia Marina Vidal.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chehboun, S., Leiva-Torres, G.A., Charbonneau, B. et al. A point mutation in the linker domain of mouse STAT5A is associated with impaired NK-cell regulation. Genes Immun 21, 136–141 (2020). https://doi.org/10.1038/s41435-019-0088-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41435-019-0088-6

Search

Advanced search

Quick links