Cell-intrinsic effects of non-MHC NOD genes on dendritic cell generation in vivo.
Genes outside the MHC create a general susceptibility to autoimmunity in non-obese diabetic (NOD) mice. Here we describe marked differences in dendritic cell generation in vivo, caused by non-MHC NOD genes. Analyses of splenic dendritic cells from the autoimmunity-prone NOD.H-2(k) mice revealed a relative over-representation of the CD8 alpha(-) subsets, in contrast to the level of these subsets observed in the autoimmunity-resistant B10.H-2(k) congenic strain or other H-2(k) strains. The imbalance towards CD8 alpha(-) dendritic cells was selectively manifested by NOD.H-2(k)-derived cells in radiation chimeras reconstituted with equal mixtures of NOD.H-2(k) and B10.H-2(k) bone marrow cells. In addition to the cell-intrinsic imbalance in dendritic cell subsets, the myeloid lineage overall was intrinsically altered by NOD genes, as this lineage was disproportionately derived from the NOD.H-2(k) donor in mixed chimeras. These results identify a striking effect of non-MHC NOD genes upon the balance of dendritic cell subsets that may contribute to the generalized defects in self-tolerance in the NOD strain.
Prasad
Simon J
SJ
Medical Genome Centre, John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia.
Goodnow
Christopher C
CC
D000818:Animals; D015551:Autoimmunity; D016827:CD8 Antigens / Q000378:metabolism; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D006183:H-2 Antigens / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance
D016827:CD8 Antigens; C431698:CD8alpha antigen; D006183:H-2 Antigens