TNFR2 Signaling Enhances ILC2 Survival, Function, and Induction of Airway Hyperreactivity

Abstract

Summary: Group 2 innate lymphoid cells (ILC2s) can initiate pathologic inflammation in allergic asthma by secreting copious amounts of type 2 cytokines, promoting lung eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. We discovered that the TNF/TNFR2 axis is a central immune checkpoint in murine and human ILC2s. ILC2s selectively express TNFR2, and blocking the TNF/TNFR2 axis inhibits survival and cytokine production and reduces ILC2-dependent AHR. The mechanism of action of TNFR2 in ILC2s is through the non-canonical NF-κB pathway as an NF-κB-inducing kinase (NIK) inhibitor blocks the costimulatory effect of TNF-α. Similarly, human ILC2s selectively express TNFR2, and using hILC2s, we show that TNFR2 engagement promotes AHR through a NIK-dependent pathway in alymphoid murine recipients. These findings highlight the role of the TNF/TNFR2 axis in pulmonary ILC2s, suggesting that targeting TNFR2 or relevant signaling is a different strategy for treating patients with ILC2-dependent asthma. : TNF-α is highly expressed in the lungs of asthmatic patients. Hurrell et al. show that murine and human ILC2s respond to TNF-α by selectively expressing TNFR2. TNF-α enhances ILC2 survival and cytokine production utilizing the non-canonical NF-κB pathway, leading to increased development of ILC2-dependent AHR. Keywords: ILC2, TNF-a, TNFR2, airway hyperreactivity, NIK, NIK inhibitor, asthma, activation