Using cultures of bone marrow cells stimulated with FMS-like tyrosine kinase 3 ligand (Flt3L), we have shown that IL-2, an autoimmune diabetes susceptibility gene in both mouse and human, inhibits DC development. IL-2 is likely acting at the MDP stage because those are the precursors that express the IL-2Ra, and MDPs accumulate in cultures with Flt3L and IL-2. We show that IL-2 acts at the developmental MDP stage, shifting development from the DC to monocyte lineage. We measured gene expression changes in DCs that develop in the presence of IL-2 and found the bim-encoding gene bcl2l11 up with IL-2 and CD135 (flt3) down with IL-2. Both of these changes were confirmed at the protein level. Furthermore, we showed that DCs that develop in the presence of IL-2 display lower phospho-STAT3 in response to Flt3L stimulation, which may explain the block in DC development. These results were published last year in the journal Immunology. We are also interested in determining how DCs differ in NOD mice compared to non-autoimmune strains, and how DCs are different in NOD mice at different diabetes pathogenesis states and disease sites. We have focused on the prediabetic phase when both pathogenic and regulatory signals are competing. Specifically, responses of 8-10 week old NOD and B6 spleen and lymph node DCs to TLRL were compared. This gives us information about both baseline and stimulated activity of DCs in mice with chronic autoimmunity but before overt disease starts. We have identified differences in the cytokine and costimulatory responses of NOD DCs. We also find that IFN-responsive genes are induced less in NOD DCs after CpG stimulation, and are following up on this to determine what pathways are responsible for this altered response, as well as what the consequences are for DC-T cell interactions and diabetes pathogenesis.

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Support Year
8
Fiscal Year
2015
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Name
U.S. National Inst Diabetes/Digst/Kidney
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Audiger, Cindy; Rahman, M Jubayer; Yun, Tae Jin et al. (2017) The Importance of Dendritic Cells in Maintaining Immune Tolerance. J Immunol 198:2223-2231
Dong, Matthew B; Rahman, M Jubayer; Tarbell, Kristin V (2016) Flow cytometric gating for spleen monocyte and DC subsets: differences in autoimmune NOD mice and with acute inflammation. J Immunol Methods 432:4-12
Rahman, M Jubayer; Rahir, Gwendoline; Dong, Matthew B et al. (2016) Despite Increased Type 1 IFN, Autoimmune Nonobese Diabetic Mice Display Impaired Dendritic Cell Response to CpG and Decreased Nuclear Localization of IFN-Activated STAT1. J Immunol 196:2031-40
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