Mapping Data

Experiment

• Experiment
  TEXT-QTL
• Chromosome
  1
• Reference
  J:106844 Lundholm M, et al., Defective induction of CTLA-4 in the NOD mouse is controlled by the NOD allele of Idd3/IL-2 and a novel locus (Ctex) telomeric on chromosome 1. Diabetes. 2006 Feb;55(2):538-44
• ID
  MGI:3639485

Genes

Gene	Assay Type
Ctex	visible phenotype
D1Mit353	PCR amplified length variant
D1Mit104	PCR amplified length variant
D1Mit403	PCR amplified length variant
Cd247	reported elsewhere
Pdcd1	reported elsewhere
Bcl2	reported elsewhere

Notes

• Experiment
  Loci linked to Ctla4 expression in CD4+CD69+ and CD8+CD69+ T-cells were mapped in 196 (NOD x C57BL/6)F2 intercross animals. 119 microsatellite markers were used for the genome scan. Nonobese diabeteic parental strain NOD exhibits defective Ctla4 expression in CD3 activated T-cells compared to parental strain C57BL/6.
  
  Ctex (Ctla4 expression) mapped to distal mouse Chromosome 1 near D1Mit353 (92.3 cM; LOD=6.5) in linkage to Ctla4 expression in CD4+ T-cells. This locus also shows significant linkage to Ctla4 expression in CD8+CD69+ T-cells with LOD=9.8. The Ctex QTL interval spans a 21 cM region between D1Mit104 (79 cM) and D1Mit403 (100 cM). Ctex was confirmed in a congenic line carrying C57BL/6-derived DNA from D1Mit411 (18.5 cM) to D1Mit403 (100 cM) ona NOD genetic background. The congenic interval includes Idd5a (38.5 cM), Idd5b (41 cM), and Ctex. Congenic animals exhibit intermediate or fully restored Ctla4 expression in CD4+ and CD8+ T-cells thus confirming the effect of Ctex. This observation suggests that NOD-derived alleles at Ctex confer decreased Ctla4 expression whereas C57BL/6-derived alleles at Ctex restores Ctla4 expression in activated T-cells. Previously identified QTL mapping near Ctex include Mbis1 (81.6 cM), Tcdel1, and Nktcn1 (87.9 cM). Potential candidate genes for Ctex include Cd247 (formerly Cd3z; 87.2 cM), Pdcd1, and Bcl2 (59.8 cM). The Idd5a/Idd5b region appears to influence in vitro ICOS expression in activated NOD spleen T-cells. Inbred strain NOD exhibits increased ICOS expression compared to C57BL/6. Congenic animals carrying C57BL/6-derived alleles at Idd5a and Idd5b on an NOD genetic background express ICOS at levels similar to the C57BL/6 donor.
  
  Suggestive linkage to Ctla4 expression in CD4+CD69+ and CD8+CD69+ T-cells mapped to mouse Chromosome 3 between D3Mit164 (2.4 cM) and D3Mit95 (22 cM). This locus contains previously identified diabetes QTL Idd3 (19.2 cM). This locus was confirmed in congenic animals carrying C57BL/6-derived DNA from D3Mit167 (16.5 cM) to D3Mit94 (22 cM), which encompasses Idd3, on a NOD genetic background. Congenic animals exhibit intermediate or fully restored Ctla4 expression in CD4+ and CD8+ T-cells thus confirming the effect of Idd3. This observation suggests that NOD-derived alleles at Idd3 confer decreased Ctla4 expression whereas C57BL/6-derived alleles at Idd3 restores Ctla4 expression in activated T-cells. Il2 (19.2 cM) is a potential candidate gene for Idd3. Addition of recombinant IL2 to activated NOD-derived spleen cultures increased the percentage of Ctla4-expressing CD8+ T-cells but did not increase the percentage of Ctla4-expressing CD4+ T-cells.