title: Unmasking genes in a type 1 diabetes-resistant mouse strain that enhances pathogenic CD8 T-cell responses.
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.
  
  
  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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Driver
authors.forename: Yi-Guang
authors.initials: YG
authors.lastname: Chen
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
authors.forename: Seblewongel
authors.initials: S
authors.lastname: Asrat
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D033481:Chromosomes, Mammalian / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic