Search

Basophils are innate immune cells associated with type 2 immunity, allergic reactions, and host defense against parasite infections. In this study, we show that the transcription factor PLZF, which is known for its essential role in the function and development of several innate lymphocyte subsets, is also important for the myeloid-derived basophil lineage. PLZF-deficient mice had decreased numbers of basophil progenitors in the bone marrow and mature basophils in multiple peripheral tissues. Functionally, PLZF-deficient basophils were less responsive to IgE activation and produced reduced amounts of IL-4. The altered function of basophils resulted in a blunted Th2 T cell response to a protein allergen. Additionally, PLZF-deficient basophils had reduced expression of the IL-18 receptor, which impacted migration to lungs. PLZF, therefore, is a major player in controlling type 2 immune responses mediated not only by innate lymphocytes but also by myeloid-derived cells.

Type 2 cytokine responses are necessary for the development of protective immunity to helminth parasites but also cause the detrimental inflammation associated with allergies and asthma. Recent studies have found that peripheral hematopoietic progenitor cell populations contribute to type 2 cytokine-mediated inflammation through their enhanced ability to develop into mast cells. Here we identify that carbonic anhydrase (Car) enzymes are upregulated in type 2-asscoaited progenitor cells and demonstrate that Car enzyme inhibition was sufficient to prevent murine mast cell development, type 2 cytokine-mediated inflammation and protective immunity to Trichinella spiralis. Moreover, we show that Car enzyme inhibition was also sufficient to prevent intestinal mast cell responses in a murine model of food allergy-like disease. Finally, we performed translational studies and demonstrated that Car enzymes can be targeted with an FDA-approved inhibitor to prevent human mast cell development. Collectively these studies identify a previously unrecognized role for Car enzymes in regulating mast cell lineage commitment and suggest that FDA-approved Car enzyme inhibitors may possess additional off-label therapeutic potential that can be employed to treat mast cell-mediated inflammation.

Neutropenia is a significant risk factor for life threatening invasive fungal infections (IFI). Neutrophils are well known as important innate cells that promote the direct eradication of fungal pathogens but whether they mediate antifungal defense beyond their role as effectors is unclear. Here we demonstrate that a pulmonary infection with the clinically relevant fungal pathogen Aspergillus fumigatus induces the diversification of specialized antifungal neutrophils that are required for antifungal CCR2+ monocyte-derived dendritic cell (mo-DC) function. Selective depletion of neutrophils resulted in global transcriptional alterations of the antifungal CCR2+ monocyte response, limited mo-DC differentiation, and diminished conidiacidal activity. Impaired mo-DC antifungal activity in neutropenic mice was accompanied by significant upregulation of carbonic anhydrase 4 (Car4) expression in CCR2+ monocyte precursors. Pharmacological inhibition of Car4 with the FDA-approved drug methazolamide (MZ) rescued the antifungal response of mo-DC and protected neutropenic mice from invasive apergillosis. Thus, beyond their role as effectors, antifungal neutrophils facilitate antifungal mo-DC functions by regulating Car4 activity. Moreover, our data provide proof-of-principle evidence for the importance of carbonic anhydrases in shaping innate cell differentiation as well as for the off-label therapeutic benefit of carbonic anhydrase inhibitors to boost antifungal immunity in susceptible patient populations.