E3 Ubiquitin Ligase Cbl-B Inhibits Type 2 Innate Lymphoid Cell Development By Targeting St2 For Ubiquitination

Abstract Type 2 innate lymphoid cells (ILC2) play a crucial role in driving allergic airway inflammation, but the regulation of ILC2 development is not fully understood. Previously we have shown that E3 ubiquitin ligase Cbl-b negatively regulates Th2 response, but whether Cbl-b also regulates ILC2-mediated type 2 immunity remains to be defined. In this study, we found that Rag1−/−Cblb−/− mice are hypersensitive to inhalation of A. Fumigatus, a fungus that causes allergic asthma, as revealed by heightened airway hyperresponsiveness (AHR), increased airway inflammation, and mucus production. This hypersensitivity is associated with increased frequencies of ILC2 and eosinophils, but reduced frequency of alveolar macrophages in the lungs. Consistent with this, type 2 cytokines are also increased in the lung homogenates of Rag1−/−Cblb−/− mice. At the molecular levels, ST2 undergoes ubiquitination and proteasome-mediated degradation upon IL-33 stimulation, which is abrogated in cells expressing Cbl-b C373A mutant. Therefore, our data indicate that Cbl-b inhibits the development of ILC2 and ILC2-mediated airway inflammation by targeting ST2 for ubiquitination.