Defective maturation of myeloid dendritic cell (DC) in NOD mice is controlled by IDD10/17/18.
We previously demonstrated that adoptive transfer of NOD pancreatic lymph node (PLN) DC protected recipients from diabetes. Our recent studies showed that the tolerogenic DC population presented islet antigens and were mature myeloid DC that did not produce IL-12, suggestive of exhausted or fully mature DC. Extensive characterization of the DC population in vivo in NOD and control mice demonstrated a specific deficiency of PLN tolerogenic DC in older mice. These findings suggest autoimmunity might arise in NOD mice secondary to deficient maturation of myeloid DC to a tolerogenic state. To address this issue, we characterized maturation and function at development of bone marrow-derived myeloid DC from NOD and several control strains. We found that NOD DC were highly resistant to several maturation stimuli and maintained an immature phenotype (average % immature DC: 75% in NOD versus 15% in B6, p < 0.01). A survey of congenic NOD mice with various NOD diabetes susceptibility loci demonstrated that the IDD10/17/18 region on chromosome 3 controlled approximately 50% of the NOD DC maturation defect. The defect also affected NOD DC that underwent phenotypic maturation. These cells appeared to arrest in a "maturing" phase as they produced 5- to 7-fold more IL-12 than control strains and significantly less IL-10. The cytokine defect was completely corrected in NOD IDD10/17/18 mice. In addition, the IDD10/17/18 locus limited DC accumulation in islets and significantly increased tolerogenic DC in the PLN. Together, the above findings suggest that polygenic regulation of DC maturation defects in NOD mice promotes islet inflammation while limiting the generation of tolerogenic DC.
Peng
Ruihua
R
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida 32608, USA.
Bathjat
K
K
Li
Y
Y
Clare-Salzler
M J
MJ
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D003713:Dendritic Cells / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology*; D005260:Female; D051379:Mice; D016688:Mice, Inbred NOD
D016207:Cytokines