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The NOD allele of the Idd5 locus on chromosome 1 mediates a non-cell-autonomous defect in negative selection of T cells.
Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Clinical Microbiology, Immunology/Immunchemistry.
Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
2007 (English)In: Journal of Autoimmunity, ISSN 0896-8411, Vol. 28, no 4, 216-223 p.Article in journal (Refereed) Published
Abstract [en]

Recent data have suggested that non-obese diabetic (NOD) mice display a defect in negative thymic selection. Using mixed bone marrow chimeras, we demonstrate that the NOD allele of the diabetes susceptibility region 5 (Idd5) locus on chromosome 1, confers defective negative selection in response to endogenous superantigens (SAg) Mtv8 and Mtv9. We generated mixed bone marrow (BM) chimeras in which the donor cells of NOD and C3H or NOD.Idd5(b10) and C3H coexist and are similarly exposed to the Mtv8 and Mtv9 SAg. Under these conditions, SAg-mediated deletion of Vbeta11+ T cells is less efficient in chimeric mice reconstituted with NOD+C3H BM, compared with chimeras reconstituted with NOD.Idd5(b10)+C3H BM. Interestingly, the observed discrepancy was not T cell autonomous but was found to be mediated by a BM derived cellular subset, and under control of a gene(s) in the Idd5 region.

Place, publisher, year, edition, pages
2007. Vol. 28, no 4, 216-223 p.
Keyword [en]
Alleles, Animals, Antigens; Viral/genetics/immunology, Bone Marrow/immunology, Chromosomes/*genetics/immunology, Diabetes Mellitus; Type 1/*genetics/immunology, Mice, Mice; Inbred NOD, Quantitative Trait Loci/genetics, Receptors; Antigen; T-Cell; alpha-beta, Species Specificity, Superantigens/genetics/immunology, T-Lymphocytes/immunology, Thymus Gland/immunology, Transplantation Chimera/genetics/immunology
URN: urn:nbn:se:umu:diva-7759DOI: 10.1016/j.jaut.2007.03.001PubMedID: 17449224OAI: diva2:147430
Available from: 2008-01-12 Created: 2008-01-12 Last updated: 2009-10-07Bibliographically approved
In thesis
1. The genetic basis of T and B cell contribution to autoimmune diabetes in NOD mice
Open this publication in new window or tab >>The genetic basis of T and B cell contribution to autoimmune diabetes in NOD mice
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The nonobese diabetic mouse (NOD) is an excellent animal model to study type 1 diabetes. As with some humans, disease in the NOD mouse is effected by a combination of genetic and environmental factors. At least 20 insulin dependent diabetes (Idd) susceptibility loci have been identified so far, both in humans and in the NOD mouse.

In this thesis, the overall aim has been to understand the genetic basis of diabetes in the NOD mouse by assessing immunogically-related phenotypes. As lymphocytes are the main players in the onset and progression to overt diabetes, we searched for physiological abnormalities in T and B cells, which could contribute to the breakdown of tolerance to pancreatic antigens. Ultimately, we postulate that abnormalities in the T or B cell compartments, under the genetic control of a previously defined diabetes susceptibility regions (Idds) could unravel the biological mechanisms underlying diabetes susceptibility and facilitate the identification of etiological polymorphisms involved in the disease.

NOD T cells are defective in upregulating CTLA-4 upon in vitro activation. Previous studies have shown that this defect is, at least in part, controlled by gene(s) in the Idd5 region on chromosome 1. In paper I, we provide evidence that defective upregulation of the CTLA-4 in NOD T cells is not controlled by the Idd5.1 and Idd5.2 regions, but rather by genes linked to the telomeric region of chromosome 1 and to the Idd3 locus, for which the prime candidate gene is Il-2. Interestingly, we could restore some of the defective CTLA-4 expression in NOD T cells by the addition of exogenous IL-2 during T cell activation in vitro. In paper II, we show that NOD thymocytes are resistant to superantigen-mediated negative selection and that this trait is under control of the Idd5.2 region. Interestingly, it appears to operate in a T cell non-autonomous manner. In paper III, we describe a competitive advantage of NOD thymocytes to mature when they co-develop with B6 thymocytes in embryo aggregation chimeras. These results imply that defects exist in the positive/negative selection mechanisms in the NOD thymus. Apart from T cells, B cells also play an important role in the initiation of diabetes in NOD mice, probably as antigen presenting cells. In paper IV, we report that the genetic basis of an enlarged marginal zone (MZ) B cell population observed in the NOD mice is linked to the Idd9/Idd11 region. Together, these findings contribute to the dissection of the molecular mechanisms underlying diabetes pathogenesis, and shed light on the contribution of central and peripheral tolerance mechanisms to this process.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2006. 108 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1015
Type 1 Diabetes, NOD mouse, CTLA-4, superantigen, T cells, Idd, marginal zone B cells, embryo aggregation chimera, negative selection
National Category
Immunology in the medical area
urn:nbn:se:umu:diva-728 (URN)91-7264-006-5 (ISBN)
Public defence
2006-03-31, Betula, 6M, Norrlands Universitetssjukhuset,, Umeå, 09:00 (English)
Available from: 2006-03-14 Created: 2006-03-14 Last updated: 2009-10-15Bibliographically approved

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