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A locus on mouse chromosome 13 inversely regulates CD1d expression and the development of invariant natural killer T-cells

Genes & Immunity volume 16, pages 221–230 (2015)Cite this article

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Abstract

Invariant natural killer T (iNKT)-cell development is controlled by many polymorphic genes present in commonly used mouse inbred strains. Development of type 1 diabetes (T1D) in NOD mice partly results from their production of fewer iNKT-cells compared with non-autoimmune-prone control strains, including ICR. We previously identified several iNKT-cell quantitative trait genetic loci co-localized with known mouse and human T1D regions in a (NOD × ICR)F2 cross. To further dissect the mechanisms underlying the impaired iNKT-cell compartment in NOD mice, we carried out a series of bone marrow transplantation as well as additional genetic mapping studies. We found that impaired iNKT-cell development in NOD mice was mainly due to the inability of their double-positive (DP) thymocytes to efficiently select this T-cell population. Interestingly, we observed higher levels of CD1d expression by NOD than by ICR DP thymocytes. The genetic control of the inverse relationship between the CD1d expression level on DP thymocytes and the frequency of thymic iNKT-cells was further mapped to a region on chromosome 13 between 60.12 and 70.59 Mb. The NOD allele was found to promote CD1d expression and suppress iNKT-cell development. Our results indicate that genetically controlled physiological variation of CD1d expression levels modulates iNKT-cell development.

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Acknowledgements

We are grateful to the NIH tetramer core facility for providing us CD1d tetramers. This work was supported by the National Institutes of Health grants DK077443 and AI110963 (to Y-GC), DK46266 and DK95735 (to DVS), as well as by grants from the Helmsley Charitable Trust (2014PG-T1D048 to DVS), The Juvenile Diabetes Research Foundation, The American Diabetes Association and the Children’s Hospital of Wisconsin Foundation.

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Authors and Affiliations

  1. Human and Molecular Genetics Center, Medical College of Wisconsin, WI, Milwaukee, USA

    S-W Tsaih, S Khaja, A E Ciecko & Y-G Chen

  2. The Jackson Laboratory, Bar Harbor, ME, USA

    M Presa & D V Serreze

  3. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    S Khaja, A E Ciecko & Y-G Chen

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  1. S-W Tsaih
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Correspondence to Y-G Chen.

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Tsaih, SW., Presa, M., Khaja, S. et al. A locus on mouse chromosome 13 inversely regulates CD1d expression and the development of invariant natural killer T-cells. Genes Immun 16, 221–230 (2015). https://doi.org/10.1038/gene.2014.81

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