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-2k 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-2k mice. This was due to failure to pass through successive rounds of cell division and elevated levels of apoptosis in NOD.H-2k precursor cells. This aberrant response to GM-CSF and IL-4 was unique to the NOD.H-2k background when compared to bone marrow cells from other H-2k 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-2k 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.
Prasad
Simon J
SJ
Medical Genome Centre, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
Goodnow
Christopher C
CC
D000818:Animals; D001854:Bone Marrow Cells / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005802:Genes, MHC Class II; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D009765:Obesity / Q000235:genetics
D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor