Novel Mechanisms In Dendritic Cells That Promote Th2 and Th17 But Not Th1 Responses In The Lung

Dendritic cells (DCs) are integral to differentiation of T helper cells into Th1, Th2 and Th17 subsets. We have dissected two novel pathways in DCs that specifically regulate CD4 T cell responses. The first is the role of the c-Kit-Phosphatidyl inositol 3 kinase (PI3 kinase)-interleukin-6 (IL-6) axis and the second that of vascular endothelial growth factor (VEGF). IL-6 plays a central role in regulating CD4 T cell immune responses by limiting a Th1 response and promoting Th2 and Th17 responses. We investigate pathways in DCs that promote IL-6 production and show that the allergen house dust mite or the mucosal adjuvant cholera toxin but not Th1-inducing adjuvant, CpG oligodeoxynucleotide (ODN) promote cell surface expression of c-kit and its ligand, stem cell factor (SCF), in DCs. This dual upregulation of c-kit and SCF results in sustained PI3-kinase signaling promoting IL-6 secretion. Intranasal administration of antigen into c-kit mutant mice or neutralization of IL-6 blunted Th2 and Th17 but promoted Th1 responses in lung-draining lymph nodes. DCs lacking functional c-kit elicit diminished allergic airway inflammation when adoptively transferred into mice. Expression of the Notch ligand, Jagged-2, which has been associated with Th2 differentiation, was reduced in DCs from c-kit mutant mice. DCs generated from mice expressing a catalytically inactive form of the p110ƒÔ (p110D910A) subunit of PI3-kinase secrete lower levels of IL-6 upon stimulation with CT. These results collectively highlight the importance of the c-kit-PI3-kinase-IL-6 signaling axis in DCs in regulating T cell responses.We also investigated mechanisms underlying the production of VEGF, which has been recently shown to be a Th2-skewing cytokine and to promote allergic asthma. We found that CT-stimulated DCs secrete high levels of VEGF while LPS induces minimal VEGF production. Activation of iNOS, NF-ƒÛB and PI3 kinase enhanced production of VEGF in DCs whereas IL-12, a Th1-skewing cytokine, inhibited VEGF production. This mechanism highlights a critical but previously unknown role for DC-derived VEGF. Taken together, these findings broaden our understanding of diverse mechanisms in DCs that enable T cell polarization and offer novel targets for therapeutic interventions