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.
|Guerrero, Alan D; Dong, Matthew B; Zhao, Yongge et al. (2014) IL-2-mediated inhibition of DC development correlates with decreased flt3 expression and increased monocyte-macrophage precursors. Immunology :|