Intrinsic in vitro abnormalities in dendritic cell generation caused by non-MHC non-obese diabetic genes

Genes outside the MHC create a general susceptibility to autoimmunity in non-obese diabetic (NOD) mice. In this study, we describe marked differences in dendritic cell generation, in vitro, caused by non-MHC NOD genes. Bone marrow cells from NOD.H-2^k mice cultured in vitro with GM-CSF and IL-4 generated a reduced yield of dendritic cells when compared to bone marrow cells from B10.H-2^k mice. This was due to failure to pass through successive rounds of cell division and elevated levels of apoptosis in NOD.H-2^k precursor cells. This aberrant response to GM-CSF and IL-4 was unique to the NOD.H-2^k background when compared to bone marrow cells from other H-2^k congenic strains, and coculture experiments showed that it was cell-autonomous. Overall, the results described in this study demonstrate a striking effect of non-MHC NOD genes on dendritic cell generation from myeloid precursors derived from the NOD.H-2^k strain. These results identify a useful genetic model to explore the regulation of dendritic cell formation. Conceivably, the dysregulation of the dendritic cell system described here may contribute to the generalized defects in self-tolerance in the NOD strain.