Dendritic cell subsets in autoimmune diabetes

利用fms样酪氨酸激酶3配体（Flt3L）刺激骨髓细胞培养，我们发现小鼠和人类自身免疫性糖尿病易感基因IL-2抑制DC的发展。IL-2可能在MDP阶段起作用，因为它们是表达IL-2Ra的前体，而MDPs在Flt3L和IL-2的培养中积累。此外，我们发现当将IL2添加到Flt3L BMDC培养物中时，单核细胞和巨噬细胞的前体增加，这表明IL2可以将DC的发育转变为单核细胞谱系。我们现在有数据显示，在IL-2存在的情况下，糖尿病易感NOD小鼠和糖尿病抵抗B6对照小鼠的dc基因表达发生了变化。

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. In addition, we find that when IL2 is added to Flt3L BMDC cultures, the precursor of monocytes and macrophages increases, suggesting that IL2 can shift development from the DC to monocyte lineage. We now have data showing gene expression changes in DCs that develop in the presence of IL-2, comparing both the diabetes susceptible NOD mice to diabetes resistant B6 control mice. 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 started by comparing responses of 8-10 week old NOD and B6 spleen and lymph node DCs to TLRL. This gives us information about both baseline and stimulated activity of DCs in mice with chronic autoimmunity but before overt disease initiates. Readouts include gene expression analysis, flow cytometry and elisa. We are finding differences in the cytokine and costimulatory responses of NOD DCs and are now determining what signaling pathways may be involved in these altered responses.