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B Activation in Nonobese Diabetic Mouse Dendritic Cells Results in Enhanced APC Function1
,
,
*
Curriculum in Genetics and Molecular Biology, School of Medicine,
Lineberger Comprehensive Cancer Center, and Departments of
Microbiology and Immunology and
Biology, University of North Carolina, Chapel Hill, NC 27599
We have recently demonstrated that dendritic cells (DC) prepared
from nonobese diabetic (NOD) mice, a spontaneous model for
insulin-dependent diabetes mellitus, exhibit elevated levels of NF-
B
activation upon stimulation. In the current study, we investigated the
influence of dysregulation of NF-B activation on the APC function of
bone marrow-derived DC prepared from NOD vs BALB/c and nonobese
diabetes-resistant mice. NOD DC pulsed with either peptide or virus
were found to be more efficient than BALB/c DC at stimulating in vitro
naive Ag-specific CD8+ T cells. The T cell stimulatory
capacity of NOD DC was suppressed by gene transfer of a modified form
of IB
, indicating a direct role for NF-B in this process.
Furthermore, neutralization of IL-12(p70) to block autocrine-mediated
activation of DC also significantly reduced the capacity of NOD DC to
stimulate T cells. Despite a reduction in low molecular mass
polypeptide-2 expression relative to BALB/c DC, no effect on
proteasome-dependent events associated with the NF-B signaling
pathway or Ag processing was detected in NOD DC. Finally, DC from
nonobese diabetes-resistant mice, a strain genotypically similar to NOD
yet disease resistant, resembled BALB/c and not NOD DC in terms of the
level of NF-B activation, secretion of IL-12(p70) and TNF-, and
the capacity to stimulate T cells. Therefore, elevated NF-B
activation and enhanced APC function are specific for the NOD genotype
and correlate with the progression of insulin-dependent diabetes
mellitus. These results also provide further evidence indicating a key
role for NF-B in regulating the APC function of
DC.
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