TNF Induces the Production of Type 2 Cytokines in Human Group 2 Innate Lymphoid Cells

Abstract

Group 2 innate lymphoid cells (ILC2s) play an important role in the initiation and amplification of type 2 inflammation by producing type 2 cytokines, including IL-5 and IL-13, and are elevated in type 2 inflammatory diseases. Recently, several studies, including our own, found that members of the TNF superfamily, TL1A and RANKL, induced production of type 2 cytokines in ILC2s. However, whether TNF itself induces type 2 cytokines in ILC2s has not been elucidated. We investigated the expression of TNF receptor II (TNFRII) on human ILC2s by flow cytometry. Purified human ILC2s sorted from either peripheral blood or nasal polyps (NPs) were stimulated with recombinant TNF and thymic stromal lymphopoietin (TSLP) in the presence or absence of inhibitors. The production of type 2 cytokines from ILC2s was evaluated by Luminex. Flow cytometric analysis revealed the expression of TNFRII on human ILC2 (n=6). TNF dose-dependently induced production of IL-5 and IL-13 in human blood ILC2s. We also found that TNF enhanced production of type 2 cytokines in NP-derived ILC2s. Interestingly, TSLP synergistically enhanced TNF mediated production of type 2 cytokines in blood ILC2s (3-fold, n=10, p<0.01). We also found that TNF-mediated production of type 2 cytokines was significantly inhibited by dexamethasone and IMD-0354 (an IKKβ inhibitor), indicating that NF-κB is a key transcription factor controlling TNF mediated production of type 2 cytokines in ILC2s. Local elevation of TNF and TSLP in tissues undergoing accumulation of ILC2s may lead to ILC2 activation and play an important role in type 2 inflammatory diseases.