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.