The Gene Expression Profile of CD11c(+)CD8 alpha(-) Dendritic Cells in the Pre-Diabetic Pancreas of the NOD Mouse

Wouter Beumer, Jojanneke Coppens, Corine Van Helden - Meeuwsen, SM Gibney, Hemmo Drexhage, Marjan Versnel

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Two major dendritic cell (DC) subsets have been described in the pancreas of mice: The CD11c(+)CD8 alpha(-) DCs (strong CD4+ T cell proliferation inducers) and the CD8 alpha(+)CD103(+) DCs (T cell apoptosis inducers). Here we analyzed the larger subset of CD11c(+)CD8 alpha(-) DCs isolated from the pancreas of pre-diabetic NOD mice for genome-wide gene expression (validated by Q-PCR) to elucidate abnormalities in underlying gene expression networks. CD11c(+)CD8 alpha(-) DCs were isolated from 5 week old NOD and control C57BL/6 pancreas. The steady state pancreatic NOD CD11c(+)CD8 alpha(-) DCs showed a reduced expression of several gene networks important for the prime functions of these cells, i.e. for cell renewal, immune tolerance induction, migration and for the provision of growth factors including those for beta cell regeneration. A functional in vivo BrdU incorporation test showed the reduced proliferation of steady state pancreatic DC. The reduced expression of tolerance induction genes (CD200R, CCR5 and CD24) was supported on the protein level by flow cytometry. Also previously published functional tests on maturation, immune stimulation and migration confirm the molecular deficits of NOD steady state DC. Despite these deficiencies NOD pancreas CD11c(+)CD8 alpha(-) DCs showed a hyperreactivity to LPS, which resulted in an enhanced pro-inflammatory state characterized by a gene profile of an enhanced expression of a number of classical inflammatory cytokines. The enhanced up-regulation of inflammatory genes was supported by the in vitro cytokine production profile of the DCs. In conclusion, our data show that NOD pancreatic CD11c(+)CD8 alpha(-) DCs show various deficiencies in steady state, while hyperreactive when encountering a danger signal such as LPS.
Original languageUndefined/Unknown
JournalPLoS One (print)
Issue number8
Publication statusPublished - 2014

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