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Unmasking genes in a type 1 diabetes-resistant mouse strain that enhances pathogenic CD8 T-cell responses. Diabetes 2011 Apr;60(4):1354-9

Date

02/11/2011

Pubmed ID

21307079

Pubmed Central ID

PMC3064110

DOI

10.2337/db10-0885

Scopus ID

2-s2.0-79953226996   2 Citations

Abstract

OBJECTIVE: Nominally resistant mouse strains such as C57BL/6 (B6) harbor latent type 1 diabetes susceptibility genes uncovered in outcross to disease-susceptible NOD mice. However, identification of possible recessively acting B6-derived susceptibility genes is limited because very few F2 progeny derived from outcrossing this strain with NOD develop spontaneous autoimmune diabetes. Thus, we assessed whether a transgenic T-cell receptor (TCR) disease transfer model allowed the mapping of recessively acting B6 genetic loci that in the proper context contribute to diabetes.

RESEARCH DESIGN AND METHODS: CD8 T-cells transgenically expressing the diabetogenic AI4 TCR were transferred into 91 (NODxB6.H2(g7))F1xB6.H2(g7) first-backcross (BC1) females. A genome-wide scan was performed for loci affecting clinical diabetes and insulitis severity.

RESULTS: A major locus on chromosome 11 in tight linkage with the marker D11Mit48 (logarithm of odds score = 13.2) strongly determined whether BC1 progeny were susceptible to AI4 T-cell-mediated diabetes. Mice homozygous versus heterozygous for B6 markers of this chromosome 11 genetic locus were, respectively, highly susceptible or resistant to AI4-induced insulitis and diabetes. The genetic effect is manifest by host CD4 T-cells. Microarray analyses of mRNA transcript expression identified a limited number of candidate genes.

CONCLUSIONS: The distal region of chromosome 11 in B6 mice harbors a previously unrecognized recessively acting gene(s) that can promote autoreactive diabetogenic CD8 T-cell responses. Future identification of this gene(s) may further aid the screening of heterogeneous humans at future risk for diabetes, and might also provide a target for possible disease interventions.

Author List

Driver JP, Chen YG, Zhang W, Asrat S, Serreze DV

Author

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
CD8-Positive T-Lymphocytes
Chromosomes, Mammalian
Diabetes Mellitus, Type 1
Female
Genetic Linkage
Genetic Predisposition to Disease
Genotype
Mice
Mice, Inbred NOD
Mice, Transgenic