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

Michael Berger, Philippe Krebs, Karine Crozat, Xiaohong Li, Ben A. Croker, Owen M. Siggs, Daniel Popkin, Xin Du, Brian R. Lawson, Argyrios N. Theofilopoulos, Yu Xia, Kevin Khovananth, Eva Marie Y. Moresco, Takashi Satoh, Osamu Takeuchi, Shizuo Akira, Bruce Beutler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

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.

Original languageAmerican English
Pages (from-to)335-343
Number of pages9
JournalNature Immunology
Volume11
Issue number4
DOIs
StatePublished - 2010
Externally publishedYes

Bibliographical note

Funding Information:
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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