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CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Endocrine Research Unit, Wallenberg Laboratory, Malmö University Hospital MAS, University of Lund, 205 02 Malmö Sweden.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
INSERM U25, Hopital Necker, Paris, France.
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2001 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 16, no 2, p. 105-113Article in journal (Refereed) Published
Abstract [en]

The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.

Place, publisher, year, edition, pages
Elsevier, 2001. Vol. 16, no 2, p. 105-113
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-87510DOI: 10.1006/jaut.2000.0474ISI: 000167547100003PubMedID: 11247636OAI: oai:DiVA.org:umu-87510DiVA, id: diva2:709608
Available from: 2014-04-02 Created: 2014-04-02 Last updated: 2019-01-21Bibliographically approved
In thesis
1. A sub-phenotype approach to dissect the genetic control of murine type 1 diabetes
Open this publication in new window or tab >>A sub-phenotype approach to dissect the genetic control of murine type 1 diabetes
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The non-obese diabetic (NOD) mouse is a model for human type 1 diabetes (T1D). The disease in the NOD mouse is polygenic and multifactorial and so far at least 20 insulin dependent diabetes (Idd) susceptibility loci have been identified. However, no etiological mutations have been definitely ascribed to the Idd loci. To identify potential etiological mutations, a sub-phenotype approach was undertaken, consisting of the establishment and genetic mapping of immuno-related sub-phenotypes that may contribute to the pathogenesis of T1D in the NOD mouse model. This thesis presents (1) the results of the identification and genetic mapping of four novel NOD immuno-phenotypes to individual Idd loci, and (2) confirmation of these results by the generation and analysis of congenic strains covering those Idd regions.

Evidence is provided that gene(s) within the Idd5 region control cyclophosphamide (CY)-induced apoptosis in peripheral lymphocytes and y-irradiation induced apoptosis in NOD thymocytes. Analysis of non-obese resistant (NOR) and NOD-Idd5 congenic mice reveal that CY-induced apoptosis in peripheral lymphocytes and y-irradiation induced apoptosis in thymocytes are controlled by a 20cM and a 6cM region, respectively, both containing the Idd5 region and including the immuno-regulatory Ctla4 gene. Additionally, CTLA4 is shown to be defectively up-regulated in activated NOD peripheral lymphocytes, and CTLA4-deficient mice show similar defects in T cell apoptosis induction. Taken together, these results suggest that a defective up-regulation of CTLA4 mediates apoptosis resistance, contributing to diabetes pathogenesis.

Moreover, it is shown that gene(s) within the Idd6 region control low proliferation ofNOD immature thymocytes and resistance to dexamethazone-induced apoptosis in immature DP thymocytes. The decrease of diabetes incidence and the restoration of the apoptosis resistance phenotype in reciprocal Idd6 congenic strains further restrict the chromosomal region controlling the Idd6 locus as well as the locus controlling the apoptosis resistance phenotype. In fact, analysis of NOD-Idd6 congenic mice reveal that Dxm-induced apoptosis in thymocytes is controlled by the distal 3cM region of the Idd6 locus. As the thymic selection process is highly dependent on both proliferation and apoptosis, the hypothesis is raised that the Idd6 locus contributes to the pathogenesis of diabetes by altering thymic selection, resulting in an autoimmune prone peripheral T cell repertoire.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2002. p. 62
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-148283 (URN)91-7305-257-4 (ISBN)
Public defence
2002-05-02, Lecture Hall "Major Groove", Dept. of Molecular Biology, Umeå, 10:00 (English)
Opponent
Note

digitalisering@UmU

Available from: 2018-05-31 Created: 2018-05-31 Last updated: 2019-01-21Bibliographically approved

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Löfgren, AnnaLejon, KristinaHolmberg, Dan

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