Clara cell 10-kDa protein inhibits T_H17 responses through modulating dendritic cells in the setting of allergic rhinitis

Background: T_H17 responses have recently been implicated to play a role in allergic airway diseases, but their local expression in the setting of allergic rhinitis (AR) and their regulation in allergic airway diseases remain unclear. Objective: We sought to investigate the regulatory role of Clara cell 10-kDa protein (CC10), an endogenous regulator of airway inflammation, on T_H17 responses in the setting of AR. Methods: Wild-type and homozygous CC10-null mice were used to establish an ovalbumin (OVA)-induced AR model. Human recombinant CC10 was given during sensitization or challenge. T_H17 responses in human subjects and mice were examined by using flow cytometry, quantitative RT-PCR assay, immunohistochemistry, and ELISA. The direct effect of CC10 on T_H17 cells and CD11c⁺ dendritic cells (DCs) was studied by means of cell culture. Adoptive transfer was used to examine the influence of CC10-conditioned DCs on airway inflammation. The regulatory effect of CC10 on the expression of the CCL20 gene was tested by using the BEAS-2B cell line. Results: Compared with those of control subjects, T_H17 responses were enhanced in the nasal mucosa of patients with AR. CC10-null mice with AR showed enhanced T_H17 responses, and CC10 treatment significantly decreased T_H17 responses. CC10 had no direct effect on in vitro T_H17 cell differentiation. CC10 could significantly decrease the expression of OX40 ligand, IL-23, and IL-6 but enhance CD86 and TGF-β expression in DCs. Importantly, CC10 was able to inhibit T_H17 cell polarization in the presence of OVA-pulsed DCs. CC10 pretreatment inhibited T_H17 responses elicited by adoptive transfer of OVA-pulsed DCs. Furthermore, CC10 decreased the expression of CCL20 in BEAS-2B cells induced by inflammatory cytokines. Conclusion: T_H17 responses are enhanced in patients with AR, and CC10 inhibits T_H17 responses through modulation of the function of DCs.