T cell antigen receptor (TCR) signaling in CD4+CD8+ double-positive thymocytes determines cell survival and lineage commitment, but the genetic and molecular basis of this process is poorly defined. To address this issue, we used ethylnitrosourea mutagenesis to identify a previously unknown T lineage–specific gene, Themis, which is critical for the completion of positive selection. Themis contains a tandem repeat of a unique globular domain (called 'CABIT' here) that includes a cysteine motif that defines a family of five uncharacterized vertebrate proteins with orthologs in most animal species. Themis-deficient thymocytes showed no substantial impairment in early TCR signaling but did show altered expression of genes involved in the cell cycle and survival before and during positive selection. Our data suggest a unique function for Themis in sustaining positive selection.
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We thank K. Holmes, E. Stregevsky and B. Hague for flow sorting; D.E. Anderson for mass spectrometry; T. Myers and Q. Su for assistance with microarrays; and the staffs of the Australian Phenomics Facility, Biomedical Services Oxford, and the US National Institutes of Health Comparative Medicine Branch for animal husbandry. Supported by the US National Institutes of Health (A.L.J.); Oxford University (A.L.J.); The Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R.H.S. and M.J.L.) and National Library of Medicine (L.A.), US National Institutes of Health; the Medical Research Council (R.J.C.); the Wellcome Trust (R.J.C. and C.C.G.); the Australian Research Council Federation (C.C.G.); and the National Institute for Health Research Biomedical Research Centre Programme (R.J.C.).
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Johnson, A., Aravind, L., Shulzhenko, N. et al. Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection. Nat Immunol 10, 831–839 (2009) doi:10.1038/ni.1769
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