It is currently unknown why allergen exposure or environmental triggers in patients with mild-to-moderate asthma result in T_H2-mediated eosinophilic inflammation, whereas patients with severe asthma often present with T_H17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both T_H2 and T_H17 cell differentiation and is mediated through nuclear factor κB activation. Ablation of TNF-α–induced protein 3 (TNFAIP3), one of the crucial negative regulators of nuclear factor κB activation in myeloid cells and DCs, was shown to control DC activation.

In this study we investigated the precise role of TNFAIP3 in myeloid cells for the development of T_H2- and T_H17-cell mediated asthma.

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.

We demonstrated that reduced Tnfaip3 gene expression in DCs in either Tnfaip3^CD11c or Tnfaip3^LysM mice dose-dependently controlled development of T_H17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wild-type mice had a purely T_H2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific T_H17 cell differentiation through increased expression of the T_H17-instructing cytokines IL-1β, IL-6, and IL-23, whereas HDM-specific T_H2 cell differentiation was hampered by increased IL-12 and IL-6 production.

These data show that the extent of TNFAIP3 expression in DCs controls T_H2/T_H17 cell differentiation. This implies that reducing DC activation could be a new pharmacologic intervention to treat patients with severe asthma who present with T_H17-mediated neutrophilic inflammation.