TNF-α-induced protein 3 levels in lung dendritic cells instruct TH2 or TH17 cell differentiation in eosinophilic or neutrophilic asthma

Background: It is currently unknown why allergen exposure or environmental triggers in patients with mild-to-moderate asthma result in T(H)2-mediated eosinophilic inflammation, whereas patients with severe asthma often present with T(H)17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both T(H)2 and T(H)17 cell differentiation and is mediated through nuclear factor kappa B activation. Ablation of TNF-alpha-induced protein 3 (TNFAIP3), one of the crucial negative regulators of nuclear factor kappa B activation in myeloid cells and DCs, was shown to control DC activation. Objective: In this study we investigated the precise role of TNFAIP3 in myeloid cells for the development of T(H)2- and T(H)17-cell mediated asthma. Methods: We exposed mice with conditional deletion of the Tnfaip3 gene in either myeloid cells (by using the lysozyme M [LysM] promotor) or specifically in DCs (by using the Cd11c promotor) to acute and chronic house dust mite (HDM)-driven asthma models. Results: We demonstrated that reduced Tnfaip3 gene expression in DCs in either Tnfaip3(CD11c) or Tnfaip3(LysM) mice dose-dependently controlled development of T(H)17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wild-type mice had a purely T(H)2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific T(H)17 cell differentiation through increased expression of the T(H)17-instructing cytokines IL-1 beta, IL-6, and IL-23, whereas HDM-specific T(H)2 cell differentiation was hampered by increased IL-12 and IL-6 production. Conclusions: These data show that the extent of TNFAIP3 expression in DCs controls T(H)2/T(H)17 cell differentiation. This implies that reducing DC activation could be a new pharmacologic intervention to treat patients with severe asthma who present with T(H)17-mediated neutrophilic inflammation.