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

• Published in: Nature immunology Vol. 11; no. 4; pp. 335 - 343
• Main Authors: Crozat, Karine, Theofilopoulos, Argyrios N, Satoh, Takashi, Akira, Shizuo, Popkin, Daniel, Lawson, Brian R, Moresco, Eva Marie Y, Beutler, Bruce, Li, Xiaohong, Takeuchi, Osamu, Siggs, Owen M, Berger, Michael, Xia, Yu, Du, Xin, Krebs, Philippe, Croker, Ben A, Khovananth, Kevin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2010; Nature Publishing Group
• Subjects: 631/208/727/2000; 631/80/641/2350; 631/80/82/23; 692/699/249/1570; Animals; Apoptosis; Apoptosis - immunology; Base Sequence; Biomedical and Life Sciences; Biomedicine; Cell Cycle Proteins - genetics; Cell Cycle Proteins - immunology; Cell Separation; Deoxyribonucleic acid; DNA; Ethyl nitrosourea; Flow Cytometry; Gene mapping; Gene mutations; Genetic aspects; Health aspects; Immune response; Immune system; Immunodeficiency; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunology; Infectious Diseases; Inflammation; Leukocytes, Mononuclear - immunology; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Mice; Mice, Transgenic; Monocytes; Mutation; Pathogens; Phenotype; Phenotypes; Physiological aspects; Physiology; Risk factors; Signal Transduction - immunology; T-Lymphocytes - immunology; Australia
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.1847

Quiescence must be actively maintained in cells of the immune response. Beutler and colleagues describe a new mutant mouse, elektra, with defective control of T cell and monocyte quiescence; this defect maps to Slfn2 . 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.