DCs get KITted out

Dendritic cells (DCs) coordinate T-cell responses by establishing a cytokine milieu that favours the differentiation of T helper (T_H) cells into T_H1-, T_H2- or T_H17-cell subsets. Although much is known about the cytokines that drive divergent T-cell differentiation, less is known about how antigens or allergens influence DCs to initiate a particular pathway. Now, a study published in Nature Medicine provides a new mechanism to explain how the allergen house-dust mite (HDM) and the mucosal adjuvant cholera toxin act on DCs to promote T_H2-cell differentiation, through a pathway involving the tyrosine kinase receptor KIT and interleukin-6 (IL-6).

IL-6 is a crucial regulator of T-cell differentiation, promoting T_H2- and T_H17-cell responses and inhibiting T_H1-cell responses — a T-cell bias that is characteristic of allergic diseases. Krishnamoorthy et al. show that, consistent with their association with allergic immune responses, both HDM and cholera toxin promote the release of large amounts of IL-6 and low levels of the T_H1-cell-inducing cytokine IL-12 by bone-marrow-derived DCs (BMDCs). Moreover, intranasal immunization of mice with HDM primed the T cells from the lung-draining lymph nodes towards a T_H2-type response; this effect was decreased in IL-6-deficient mice, which indicates a key role for allergen-induced IL-6 in regulating the ensuing T-cell response.

To define the mechanism underlying IL-6 upregulation by HDM and cholera toxin, the authors carried out microarray analysis to identify genes induced in DCs by cholera toxin. Together with that encoding IL-6, the gene encoding KIT was significantly upregulated in BMDCs after cholera toxin treatment. A comparison of KIT⁺ and KIT⁻ BMDCs sorted from cholera-toxin-treated cultures revealed that those expressing KIT promoted T_H2- and T_H17-cell responses, whereas KIT⁻ BMDCs favoured T_H1-cell differentiation.

Further studies confirmed that signalling through KIT in DCs is important for inducing IL-6 production, as BMDCs or lung DCs from mice expressing an inactive form of KIT (Kit^W/W-v mice) secreted lower amounts of IL-6 following in vitro stimulation with cholera toxin or HDM than did wild-type BMDCs. Moreover, following intratracheal transfer into wild-type recipients and antigen challenge, Kit^W/W-v DCs were unable to induce strong T_H2- and T_H17-cell responses and elicited less allergic airway inflammation than did wild-type BMDCs.

The authors next investigated how KIT might be stimulated to induce IL-6 production. Their analysis revealed that, similar to KIT, expression of the ligand for KIT, stem-cell factor (SCF), on the surface of BMDCs was increased in the presence of cholera toxin or HDM. SCF expression proved to be important for KIT-mediated IL-6 production, as BMDCs from mice lacking membrane-bound SCF had decreased IL-6 production after allergen stimulation. High-level expression of both KIT and SCF on allergen-stimulated DCs was shown to support persistent signalling through KIT, leading to prolonged activation of the downstream enzyme phosphoinositide 3-kinase (PI3K) and ultimately to IL-6 production. Accordingly, BMDCs from mice that lack the p110δ subunit of PI3K, which tend to be resistant to allergic airway disease, secreted less IL-6 in response to cholera toxin.

Together, these results support a model of allergen-mediated regulation of DCs, involving a KIT–PI3K–IL-6 signalling pathway that promotes T_H2- and T_H17-cell responses.