Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma

doi:doi:10.1038/nm1766

Dendritic cells (DCs) are integral to the differentiation of T helper cells into T helper type 1 T_H1, T_H2 and T_H17 subsets. Interleukin-6 (IL-6) plays an important part in regulating these three arms of the immune response by limiting the T_H1 response and promoting the T_H2 and T_H17 responses. In this study, we investigated pathways in DCs that promote IL-6 production. We show that the allergen house dust mite (HDM) or the mucosal adjuvant cholera toxin 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, promoting IL-6 secretion. Intranasal administration of antigen into c-Kit–mutant mice or neutralization of IL-6 in cultures established from the lung-draining lymph nodes of immunized wild-type mice blunted the T_H2 and T_H17 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 cholera toxin. DCs expressing nonfunctional c-Kit were unable to induce a robust T_H2 or T_H17 response and elicited diminished allergic airway inflammation when adoptively transferred into mice. Expression of the Notch ligand Jagged-2, which has been associated with T_H2 differentiation, was blunted in DCs from c-Kit–mutant mice. c-Kit upregulation was specifically induced by T_H2- and T_H17-skewing stimuli, as the T_H1-inducing adjuvant, CpG oligodeoxynucleotide, did not promote either c-Kit or Jagged-2 expression. DCs generated from mice expressing a catalytically inactive form of the p110 delta subunit of phosphatidylinositol-3 (PI3) kinase (p110_D910A) secreted lower amounts of IL-6 upon stimulation with cholera toxin. Collectively, these results highlight the importance of the c-Kit–PI3 kinase–IL-6 signaling axis in DCs in regulating T cell responses.

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