Lung epithelium is the major source of IL-33 and is regulated by IL-33-dependent and IL-33-independent mechanisms in pulmonary cryptococcosis.

Inhalation of the fungus Cryptococcus neoformans (C. neoformans) results in pulmonary cryptococcosis associated with IL-33-dependent type 2 immunity. Lung epithelium represents the initial contact site of infection. The role of IL-33 in type 2 immunity has been analyzed, but the source of this cytokine and its effect on lung epithelial cell function in pulmonary cryptococcosis remained unclear. In mice infected with C. neoformans, we identified alveolar type 2 epithelial cells as major source of IL-33. On both, IL-33-positive and IL-33-negative epithelial cells, IL-33 receptor expression was detectable. Therefore, we studied the role of IL-33 receptor expression for IL-33 synthesis during fungal infection on lung epithelial cells and found no auto-/paracrine IL-33 induction. Next, the effect of IL-33 on epithelial E-cadherin expression, a cell-to-cell adhesion molecule, was analyzed. Fungal infection resulted in E-cadherin downregulation in an IL-33-dependent manner on pulmonary epithelial cells both at the single-cell and at the population level. On the other hand, epithelial cells from infected mice upregulated surfactant protein C (SP-C) and CXCL15 mRNA production together with but independently of IL-33. In conclusion, lung epithelium represents a significant source of IL-33 in pulmonary cryptococcosis and is regulated in an IL-33-dependent but also IL-33-independent manner.

Therapeutic expansion of CD4+FoxP3+ regulatory T cells limits allergic airway inflammation during pulmonary fungal infection.

Allergic asthma can be frequently caused and exacerbated by sensitization to ubiquitous fungal allergens associated with pulmonary mucus production, airway hyperresponsiveness and bronchial constriction, resulting in a complex disease that is often difficult to treat. Fungal infections are frequently complicated by the development of a type 2 immune response that prevents successful elimination of the fungal pathogen. Furthermore, production of type 2 cytokines triggers allergic airway inflammation. Following intranasal infection of BALB/c mice with the fungusCryptococcus neoformans, we recently described a more pronounced type 2 immune response in the absence of regulatory T (Treg) cells. To determine whether Treg cell expansion is able to suppress type 2-related fungal allergic inflammation, we increased Treg cell numbers during pulmonaryC. neoformansinfection by administration of an interleukin (IL)-2/anti-IL-2 complex. Expansion of Treg cells resulted in reduced immunoglobulin E production and decreased allergic airway inflammation including reduced production of pulmonary mucus and type 2 cytokines as well as production of immunosuppressive cytokines such as IL-10 and transforming growth factor-ß1. From our data we conclude that Treg cells and/or their suppressive mediators represent potential targets for therapeutic intervention during allergic fungal airway disease.