期刊
JOURNAL OF IMMUNOLOGY
卷 168, 期 1, 页码 188-196出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.168.1.188
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资金
- NIAID NIH HHS [5T32 AI 07273, AI 35098] Funding Source: Medline
- NIDCR NIH HHS [1P60 DE 13079] Funding Source: Medline
- NIDDK NIH HHS [5R01 DK 52365] Funding Source: Medline
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI035098, R37AI035098, T32AI007273] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [P60DE013079] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK052365] Funding Source: NIH RePORTER
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-kappaB activation upon stimulation. In the current study, we investigated the influence of dysregulation of NF-kappaB activation on the APC function of bone marrow-derived DC prepared from NOD Ns BALB/c and nonobese diabetes-resistant mice. NOD DC pulsed with either peptide or virus Acre 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 kappaB alpha, indicating a direct role for NF-kappaB 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-kappaB 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-kappaB activation, secretion of IL-12(p70) and TNF-alpha, and the capacity to stimulate T cells. Therefore, elevated NF-kappaB 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-kappaB in regulating the APC function of DC.
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