Genetic and functional analysis of the Nkt1 locus using congenic NOD mice: improved Valpha14-NKT cell performance but failure to protect against type 1 diabetes.
Defective invariant natural killer T-cells (iNKT cells) have been implicated in the etiology of type 1 diabetes in nonobese diabetic (NOD) mice. In a genome scan of a cross between NOD and C57BL/6 mice, the most significant locus controlling the number of iNKT cells, referred to as Nkt1, was recently mapped to distal chromosome 1. Here, using congenic mice for this chromosomal segment, we definitively demonstrate the existence of Nkt1 and show that introgression of the C57BL/6 allele onto the NOD background improves both the number of iNKT cells and their rapid production of cytokines elicited by alpha-galactosylceramide treatment, explaining at least half of the difference between the NOD and C57BL/6 strains. Using new subcongenic lines, we circumscribed the Nkt1 locus to a 8.7-cM segment, between the NR1i3 and D1Mit458 markers, that notably includes the SLAM (signaling lymphocytic activation molecule) gene cluster, recently involved in murine lupus susceptibility. However, despite a significant correction of the iNKT cell defect, the Nkt1 locus did not alter the course of spontaneous diabetes in congenic mice. Our findings indicate a complex relationship between iNKT cells and autoimmune susceptibility. Congenic lines nonetheless provide powerful models to dissect the biology of iNKT cells.
Rocha-Campos
Ana-Claudia
AC
Centre National de Recherche Unité Mixte de Recherche 8147, Université Paris 5, France.
Melki
Rahma
R
Zhu
Ren
R
Deruytter
Nathalie
N
Damotte
Diane
D
Dy
Michel
M
Herbelin
André
A
Garchon
Henri-Jean
HJ
D000818:Animals; D002874:Chromosome Mapping; D000090702:Constitutive Androstane Receptor; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005434:Flow Cytometry; D014644:Genetic Variation; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D013154:Spleen / Q000276:immunology