Drake, Li Y.

Abstract IL-33, an IL-1 family cytokine, is constitutively expressed in mucosal tissues and other organs in healthy humans and animals, and expression levels increase in inflammatory conditions. Although IL-33–mediated promotion of type 2 immune responses has been well established, a gap in our knowledge regarding the functional diversity of this pleiotropic cytokine remains. To address this gap, we developed a new IL-33 transgenic mouse model in which overexpression of full-length IL-33 is induced in lung epithelial cells under conditional control. In adult mice, an ∼3-fold increase in the steady-state IL-33 levels produced no pathologic effects in the lungs. When exposed to airborne allergens, adult transgenic mice released more IL-33 extracellularly and exhibited robust type 2 immune responses. In neonatal transgenic mice, up to postnatal day 14, a similar increase in steady-state IL-33 levels resulted in increased mortality, enlarged alveolar spaces resembling bronchopulmonary dysplasia, and altered expression of genes associated with tissue morphogenesis. Processed 25-kDa IL-33 protein was detected in bronchoalveolar lavage fluids without any exogenous stimuli, and pathologic changes were abolished in mice deficient in the IL-33 receptor ST2. These findings suggest that adult lungs are relatively resistant to IL-33 overexpression unless they encounter environmental insults, whereas developing lungs are highly susceptible, with IL-33 overexpression resulting in detrimental and pathologic outcomes.

Abstract Group 2 innate lymphoid cells (ILC2s) reside in multiple organs in the body, where they play roles in immunity, tissue homeostasis, and metabolic regulation. However, little is known about the regulatory mechanisms of ILC2s in different organs. Here, we identified ILC2s in the mouse uterus and found that they express cell surface molecules, including the IL-33 receptor, ST2, that are roughly comparable to those expressed by lung ILC2s. Both in vivo and in vitro treatment with IL-33 induced type 2 cytokine production in uterine ILC2s, suggesting that they respond to IL-33 in a manner similar to ILC2s in other organs. Importantly, uterine ILC2s were nearly absent in ovariectomized mice and were increased in wild-type mice by estrogen administration, whereas lung ILC2s were unaffected by both ovariectomy and estrogen administration. Likewise, a marked reduction in uterine ILC2s was observed in mice deficient in estrogen receptor α or estrogen receptor β. Furthermore, uterine ILC2s highly expressed estrogen receptor α, and in vitro culture of isolated uterine ILC2s with 17β-estradiol modified expression of a number of genes. Finally, an increased prevalence in neonatal mortality was observed in litters from dams lacking the IL-33 receptor, ST2. Taken together, our findings indicate that unlike lung IL2Cs, uterine ILC2s are regulated by female sex hormones, which may specialize them for specific physiological functions.

Summary Interleukin ( IL )‐33 is a key cytokine involved in type 2 immunity and allergic airway diseases. Abundantly expressed in lung epithelial cells, IL ‐33 plays critical roles in both innate and adaptive immune responses in mucosal organs. In innate immunity, IL ‐33 and group 2 innate lymphoid cells ( ILC 2s) provide an essential axis for rapid immune responses and tissue homeostasis. In adaptive immunity, IL ‐33 interacts with dendritic cells, Th2 cells, follicular T cells, and regulatory T cells, where IL ‐33 influences the development of chronic airway inflammation and tissue remodeling. The clinical findings that both the IL ‐33 and ILC 2 levels are elevated in patients with allergic airway diseases suggest that IL ‐33 plays an important role in the pathogenesis of these diseases. IL ‐33 and ILC 2 may also serve as biomarkers for disease classification and to monitor the progression of diseases. In this article, we reviewed the current knowledge of the biology of IL ‐33 and discussed the roles of the IL ‐33 in regulating airway immune responses and allergic airway diseases.

Abstract Innate lymphoid cells (ILCs) are a new family of immune cells that play important roles in innate immunity in mucosal tissues, and in the maintenance of tissue and metabolic homeostasis. Recently, group 2 ILCs (ILC2s) were found to promote the development and effector functions of Th2-type CD4+ T cells by interacting directly with T cells or by activating dendritic cells, suggesting a role for ILC2s in regulating adaptive immunity. However, our current knowledge on the role of ILCs in humoral immunity is limited. In this study, we found that ILC2s isolated from the lungs of naive BALB/c mice enhanced the proliferation of B1- as well as B2-type B cells and promoted the production of IgM, IgG1, IgA, and IgE by these cells in vitro. Soluble factors secreted by ILC2s were sufficient to enhance B cell Ig production. By using blocking Abs and ILC2s isolated from IL-5–deficient mice, we found that ILC2-derived IL-5 is critically involved in the enhanced production of IgM. Furthermore, when adoptively transferred to Il7r−/− mice, which lack ILC2s and mature T cells, lung ILC2s promoted the production of IgM Abs to a polysaccharide Ag, 4-hydroxy-3-nitrophenylacetyl Ficoll, within 7 d of airway exposure in vivo. These findings add to the growing body of literature regarding the regulatory functions of ILCs in adaptive immunity, and suggest that lung ILC2s promote B cell production of early Abs to a respiratory Ag even in the absence of T cells.

Abstract Background Innate lymphoid cells ( ILC s) play important roles in innate immunity and tissue remodeling via production of various cytokines and growth factors. Group 2 ILC s ( ILC 2s) were recently shown to mediate the immune pathology of asthma even without adaptive immunity. However, little is known about possible interactions between ILC 2s and other immune cells. We sought to investigate the capacity of ILC 2s to regulate effector functions of T cells. Methods We isolated ILC 2s from the lungs of naïve mice. We cultured CD 4 + T cells with ILC 2s in vitro and examined the functions of these cell types. The mechanisms were investigated using blocking antibodies and cells isolated from cytokine‐deficient mice. For the in vivo study, we adoptively transferred ILC 2s and CD 4 + T cells into Il7ra −/− mice and subsequently exposed the mice to ovalbumin and a cysteine protease. Results Lung ILC 2s enhanced CD 4 + T‐cell proliferation and promoted production of type 2 cytokines in vitro . The interaction between ILC 2s and CD 4 + T cells involved costimulatory molecule OX 40L and cytokine IL ‐4, which was mainly derived from ILC 2s. Adoptive transfer of both ILC 2 and CD 4 + T‐cell populations, but not each population alone, into Il7ra −/− mice resulted in induction of a robust antigen‐specific type 2 cytokine response and airway inflammation. Conclusion Lung ILC 2s function to promote adaptive immunity in addition to their established roles in innate immunity. This novel function of ILC 2s needs to be taken into account when considering the pathophysiology of asthma and other allergic airway diseases.