We have previously proposed that sequence variation of the CD101 gene between NOD and C57BL/6 mice accounts for the protection from type 1 diabetes (T1D) provided by the insulin-dependent diabetes susceptibility region 10 (Idd10), a <1 Mb region on mouse chromosome 3. In this study, we provide further support for the hypothesis that Cd101 is Idd10 using haplotype and expression analyses of novel Idd10 congenic strains coupled to the development of a CD101 knockout mouse. Susceptibility to T1D was correlated with genotype-dependent CD101 expression on multiple cell subsets, including Foxp3+ regulatory CD4+ T cells, CD11c+ dendritic cells, and Gr1+ myeloid cells. The correlation of CD101 expression on immune cells from four independent Idd10 haplotypes with the development of T1D supports the identity of Cd101 as Idd10. Because CD101 has been associated with regulatory T and Ag presentation cell functions, our results provide a further link between immune regulation and susceptibility to T1D.
This work was supported by Award P01AI039671 (to L.S.W. and J.A.T.) from the National Institute of Allergy and Infectious Diseases (NIAID). L.S.W. is a Wellcome Trust Principal Research Fellow. H.I.F. was funded by a Wellcome Trust 4-year studentship. L.S.W. and J.A.T. are supported by a joint grant from the Juvenile Diabetes Research Foundation (JDRF), the Wellcome Trust, and the National Institute for Health Research Biomedical Research Centre. J.M. is supported by the Lupus Research Institute, a grant from the University of Cincinnati microbial pathogenesis core center, Public Health Service Grant P30 DK078392, Award R01DK084054 from the National Institute of Diabetes and Digestive and Kidney Diseases, the German Research Foundation Deutsche Forschungsgemeinschaft (MA 2621/2-1), and the Interdisciplinary Center for Clinical Research of the Universitätsklinikum Erlangen (IZKF_JB10_A48). The Cambridge Institute for Medical Research received Wellcome Trust Strategic Award 079895. The resequencing of Idd10 using NOD bacterial artificial chromosomes was performed at the Wellcome Trust Sanger Institute and was funded by the Immune Tolerance Network Contract AI 15416, which was sponsored by the NIAID, the National Institute of Diabetes and Digestive and Kidney Diseases, and JDRF International. The availability of NOD congenic mice through the Taconic Emerging Models Program has been supported by grants from Merck Genome Research Institute, NIAID, and JDRF.
The sequences presented in this article have been submitted to the European Molecular Biology Laboratory under accession numbers AL663099, AL669922, AL669933, AL645760, AL645757, AL669937, and AL672281.
The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.
The online version of this article contains supplemental material.
- Received October 22, 2010.
- Accepted April 28, 2011.
- Copyright © 2011 by The American Association of Immunologists, Inc.