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The Journal of Immunology, 2002, 168: 188-196.
Copyright © 2002 by The American Association of Immunologists

Elevated NF-{kappa}B Activation in Nonobese Diabetic Mouse Dendritic Cells Results in Enhanced APC Function1

Brian Poligone*,{dagger}, Donald J. Weaver, Jr.{ddagger}, Pradip Sen{ddagger}, Albert S. Baldwin, Jr.*,{dagger},§ and Roland Tisch2,{dagger},{ddagger}

* Curriculum in Genetics and Molecular Biology, School of Medicine, {dagger} Lineberger Comprehensive Cancer Center, and Departments of {ddagger} 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-{kappa}B activation upon stimulation. In the current study, we investigated the influence of dysregulation of NF-{kappa}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 I{kappa}B{alpha}, indicating a direct role for NF-{kappa}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-{kappa}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-{kappa}B activation, secretion of IL-12(p70) and TNF-{alpha}, and the capacity to stimulate T cells. Therefore, elevated NF-{kappa}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-{kappa}B in regulating the APC function of DC.




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