Monocytes differentiated with GM-CSF and IL-15 initiate Th17 and Th1 responses that are contact-dependent and mediated by IL-15

Distinct types of DCs are generated from monocytes using GM-CSF with IL-4 (IL4-DC) or IL-15 (IL15-DC). IL15-DCs are potent inducers of antigen-specific CD8 T cells, display a phenotype similar to CD14 cells com-monly described in chronically inflamed tissues, and produce high levels of IL-1 and IL-15 in response to TLR4 stimulation. As these cytokines promote Th17 re-sponses, which are also associated with inflammatory diseases, I hypothesized that TLR-primed IL15-DCs fa-vor Th17 activation over IL4-DCs. Compared with IL4-DCs, IL15-DCs stimulated with TLR agonists secreted significantly higher concentrations of the Th17-promot-ing factors, IL-1, IL-6, IL-23, and CCL20, and lower lev-els of the Th1 cytokine, IL-12. In addition, IL15-DCs and not IL4-DCs up-regulated IL-15 on the cell surface in re-sponse to TLR agonists. IL15-DCs primed with TLR3 or TLR4 agonists triggered Th17 (IL-17, IL-22, and/or IFN-) and Th1 (IFN-) responses, whereas IL4-DCs primed with the same TLR agonists activated Th1 (IFN-) responses. Secretion of IL-17 and IFN- required contact with TLR-primed IL15-DC, and IFN- production was mediated by membrane-bound IL-15. These find-ings identify key differences in monocyte-derived DCs, which impact adaptive immunity, and provide primary evidence that IL-15 promotes Th17 and Th1 responses by skewing monocytes into IL15-DC. J. Leukoc. Biol. 90: 000–000; 2011