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

Cell Rep. 2019 Dec 24;29(13):4509-4524.e5. doi: 10.1016/j.celrep.2019.11.102.

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. 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.

Keywords: ILC2; NIK; NIK inhibitor; TNF-a; TNFR2; activation; airway hyperreactivity; asthma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cell Survival
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Humans
  • Lung / immunology
  • Lung / pathology
  • Lymphocyte Transfusion
  • Lymphocytes / immunology*
  • Lymphocytes / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappaB-Inducing Kinase
  • Protein Isoforms / genetics
  • Protein Isoforms / immunology
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / immunology
  • Receptors, Tumor Necrosis Factor, Type II / genetics*
  • Receptors, Tumor Necrosis Factor, Type II / immunology
  • Respiratory Hypersensitivity / genetics
  • Respiratory Hypersensitivity / immunology*
  • Respiratory Hypersensitivity / pathology
  • Signal Transduction / immunology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • NF-kappa B
  • Protein Isoforms
  • Receptors, Tumor Necrosis Factor, Type II
  • Tnfrsf1b protein, mouse
  • Tumor Necrosis Factor-alpha
  • Protein Serine-Threonine Kinases