title: Monocytes differentiated with GM-CSF and IL-15 initiate Th17 and Th1 responses that are contact-dependent and mediated by IL-15.
abstract: 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 commonly described in chronically inflamed tissues, and produce high levels of IL-1β and IL-15 in response to TLR4 stimulation. As these cytokines promote Th17 responses, which are also associated with inflammatory diseases, I hypothesized that TLR-primed IL15-DCs favor Th17 activation over IL4-DCs. Compared with IL4-DCs, IL15-DCs stimulated with TLR agonists secreted significantly higher concentrations of the Th17-promoting factors, IL-1β, IL-6, IL-23, and CCL20, and lower levels of the Th1 cytokine, IL-12. In addition, IL15-DCs and not IL4-DCs up-regulated IL-15 on the cell surface in response to TLR agonists. IL15-DCs primed with TLR3 or TLR4 agonists triggered Th17 (IL-17, IL-22, and/or IFN-γ) and Th1 (IFN-γ) responses, whereas IL4-DCs primed with the same TLR agonists activated Th1 (IFN-γ) responses. Secretion of IL-17 and IFN-γ required contact with TLR-primed IL15-DC, and IFN-γ production was mediated by membrane-bound IL-15. These findings 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.
authors: Pathology Department, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. kholt003@umaryland.edu
authors: Kristina M
authors: KM
authors: Harris
mesh_terms: D002450:Cell Communication / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D016207:Cytokines; D019409:Interleukin-15; D051193:Toll-Like Receptors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor