CD97/ADGRE5 attenuates the induction of adaptive type 2 immune responses in allergic asthma

Allergic asthma results from an uncontrolled type 2 immune response to inhaled allergens. Here, we investigate the function of CD97/ADGRE5, expressed in mouse and human immune and lung epithelial cells, in this disease. Female Cd97^-/- mice exhibit an exacerbated asthmatic phenotype across multiple models, primarily due to CD97 loss on immune cells. A single CD97 antibody treatment before allergen sensitization worsens allergic responses, highlighting a role for CD97 in early immune regulation. Post-sensitization, Cd97^-/- mice display higher frequencies of lung conventional type 2 and monocyte-derived dendritic cells (DCs). Allergen-pulsed Cd97^-/- bone marrow-derived DCs are more activated, promote enhanced proliferation and type 2 cytokine secretion by CD4⁺ OT-II cells, and induce stronger airway inflammation. Consistently, ADGRE5 expression is reduced in airway mucosa-derived mononuclear phagocyte subsets in human asthmatics after allergen-induced exacerbation. These results identify CD97 as an important regulator of DC-driven type 2 allergic responses and a potential target in asthma.