A critical role for c-kit on dendritic cells in regulating in T helper cell differentiation and allergic asthma (79.3)

Abstract

Abstract Dendritic cells are integral in instructing the differentiation of T helper cells into Th1, Th2 and Th17 subsets and IL-6 is a key regulator of CD4 T cell differentiation .In this study, we investigated pathways in DCs that promote IL-6 production. We show exposure of DCs to house dust mite (HDM) or the mucosal adjuvant cholera toxin (CT) promotes cell surface expression of c-Kit and its ligand, stem cell factor (SCF), on DCs. This dual upregulation of c-Kit and SCF results in sustained signaling downstream of c-Kit, thereby promoting IL-6 secretion. Intranasal administration of antigen into c-Kit-mutant mice or neutralization of IL-6 in cultures from the lung-draining lymph nodes of immunized wild-type mice blunted the Th2 and Th7 responses. DCs lacking functional c-Kit or those unable to express membrane-bound SCF secreted lower amounts of IL-6 in response to HDM or CT. Expression of the Th2-Notch ligand Jagged-2 was also reduced in DCs from c-Kit-mutant mice in response to CT or HDM and the Th1-inducing adjuvant, CpG oligodeoxynucleotide, did not promote either c-Kit or Jagged-2 expression. DCs expressing nonfunctional c-Kit were unable to induce a robust Th2 or Th17 response and elicited diminished allergic airway inflammation when adoptively transferred into WT mice. DCs generated from mice expressing a catalytically inactive form of the p110delta subunit of phosphatidylinositol-3 (PI3) kinase secreted lower amounts of IL-6 upon stimulation with cholera toxin. Taken together, these results reveal the importance of the c-Kit-PI3 kinase-IL-6 signaling axis in DCs in the regulation of T cell responses.