TNFR2 signaling enhances ILC2 survival, function and induction of airway hyperreactivity

Abstract

Abstract 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. TNFa is a pleiotropic proinflammatory cytokine which is elevated in the airways of patients with severe asthma, signaling through two main receptors with opposing functions: TNFR1 and TNFR2. We found that murine ILC2s selectively express and induce TNFR2 upon IL-33 activation, whereas they fail to express – or induce – TNFR1. Strikingly, blocking the TNF/TNFR2 axis inhibits ILC2 survival, cytokine production, ILC2-dependent AHR and airway eosinophilia. The mechanism of action of TNFR2 in ILC2s is through utilizing non-canonical NFkB pathway as a NFkB inducing kinase (NIK) inhibitor blocks the costimulatory effects of TNFa both in vitro and in vivo. Similarly, human ILC2s selectively express TNFR2 and using the model of humanized mice that our laboratory recently developed, we show that TNFR2 engagement in human ILC2s enhances survival and activation, ultimately promoting AHR through a NIK-dependent pathway. These findings highlight the role of the TNF/TNFR2 axis in pulmonary ILC2s, suggesting that targeting TNFR2 or relevant signaling represents a novel strategy for treating patients with ILC2-dependent asthma.