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An Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence

Nature Immunology volume 11, pages 335–343 (2010)Cite this article

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Abstract

Here we describe a previously unknown form of inherited immunodeficiency revealed by an N-ethyl-N-nitrosourea–induced mutation called elektra. Mice homozygous for this mutation showed enhanced susceptibility to bacterial and viral infection and diminished numbers of T cells and inflammatory monocytes that failed to proliferate after infection and died via the intrinsic apoptotic pathway in response to diverse proliferative stimuli. They also had a greater proportion of T cells poised to replicate DNA, and their T cells expressed a subset of activation markers, suggestive of a semi-activated state. We positionally ascribe the elektra phenotype to a mutation in the gene encoding Schlafen-2 (Slfn2). Our findings identify a physiological role for Slfn2 in the defense against pathogens through the regulation of quiescence in T cells and monocytes.

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Figure 1: Mice homozygous for the elektra mutation are highly susceptible to infection with MCMV, LCMV and L. monocytogenes.
Figure 2: Defect in peripheral T cells in elektra homozygotes.
Figure 3: Apoptosis of elektra-homozygous T cells in response to activation signals.
Figure 4: Apoptosis of elektra-homozygous T cells in response to homeostatic expansion signals.
Figure 5: T cells homozygous for the elektra mutation die via the intrinsic apoptotic pathway.
Figure 6: T cells homozygous for the elektra mutation exist in a semiactivated state.
Figure 7: Apoptosis of elektra-homozygous monocytes in response to activation signals.
Figure 8: 'Rescue' of the elektra phenotype by BAC transgenesis.

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Acknowledgements

We thank O. Milstein, J.F. Purton and K. Brandl for discussions; M.B.A. Oldstone (The Scripps Research Institute) for the Armstrong strain of LCMV; and C.D. Surh (The Scripps Research Institute) for monoclonal anti-IL-7 (M25). Supported by the European Molecular Biology Organization (M.B. and P.K.), the Swiss National Science Foundation (P.K.) and the US National Institutes of Health (PO1 AI070167-01).

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Author notes

  1. Karine Crozat & Ben A Croker

    Present address: Present addresses: Centre d'Immunologie de Marseille-Luminy, Marseille, France (K.C.) and Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia (B.A.C.).,

Authors and Affiliations

  1. Department of Genetics, The Scripps Research Institute, La Jolla, California, USA

    Michael Berger, Philippe Krebs, Karine Crozat, Xiaohong Li, Ben A Croker, Owen M Siggs, Xin Du, Yu Xia, Kevin Khovananth, Eva Marie Y Moresco & Bruce Beutler

  2. Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, USA

    Daniel Popkin, Brian R Lawson & Argyrios N Theofilopoulos

  3. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

    Takashi Satoh, Osamu Takeuchi & Shizuo Akira

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Contributions

M.B. and B.B. designed the research with critical suggestions from P.K., K.C. and A.N.T.; M.B., P.K., K.C., X.L., B.A.C., O.M.S., D.P. and B.R.L. did experiments; X.L. and X.D. generated the BAC-transgenic mice; M.B., Y.X. and K.K. did all genome mapping; T.S., O.T. and S.A. generated Slfn3−/− and Slfn1−/− mice; and M.B., E.M.Y.M. and B.B. wrote the manuscript.

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Correspondence to Bruce Beutler.

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Berger, M., Krebs, P., Crozat, K. et al. An Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence. Nat Immunol 11, 335–343 (2010). https://doi.org/10.1038/ni.1847

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