TNF-α-induced protein 3 levels in lung dendritic cells instruct T H 2 or T H 17 cell differentiation in eosinophilic or neutrophilic asthma

• Published in: Journal of allergy and clinical immunology 2018-05, Vol.141 (5), p.1620-1633.e12
• Main Authors: Vroman, Heleen, Bergen, Ingrid M, van Hulst, Jennifer A C, van Nimwegen, Menno, van Uden, Denise, Schuijs, Martijn J, Pillai, Saravanan Y, van Loo, Geert, Hammad, Hamida, Lambrecht, Bart N, Hendriks, Rudi W, Kool, Mirjam
• Format: Article
• Language: English
• Subjects: Allergens; Allergies; Animal models; Antigens; Asthma; CD11c antigen; Cell activation; Cell differentiation; Clonal deletion; Cytokines; Dendritic cells; Gene deletion; Gene expression; Genes; Helper cells; House dust; Interleukin 12; Interleukin 23; Interleukin 6; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Lipids; Lungs; Lymphocytes T; Lysozyme; Metabolism; Mice; Myeloid cells; Proteins; T cell receptors; Tumor necrosis factor-α
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2017.08.012

It is currently unknown why allergen exposure or environmental triggers in patients with mild-to-moderate asthma result in T 2-mediated eosinophilic inflammation, whereas patients with severe asthma often present with T 17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both T 2 and T 17 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 2- and T 17-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 or Tnfaip3 mice dose-dependently controlled development of T 17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wild-type mice had a purely T 2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific T 17 cell differentiation through increased expression of the T 17-instructing cytokines IL-1β, IL-6, and IL-23, whereas HDM-specific T 2 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 2/T 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 17-mediated neutrophilic inflammation.