Loss of the adhesion receptor CD97 exacerbates allergic asthma by disinhibiting dendritic cell activity in the lungs, according to a peer-reviewed study published in Nature Communications. The receptor, encoded by the ADGRE5 gene, appears on both human and mouse immune cells and lung epithelial tissue.
Researchers tested the receptor's role across acute and chronic mouse models using ovalbumin and house dust mite allergens. Female mice lacking CD97 developed increased eosinophilic airway inflammation, elevated serum IgE antibodies, higher mucus production, and greater levels of type 2 cytokines such as interleukin-5 and interleukin-13. Airway hyper-responsiveness remained unchanged in acute settings but increased during chronic exposure alongside elevated neutrophil counts and greater smooth muscle mass.
Selective deletion experiments isolated the primary protective effect to blood-forming immune cells rather than the lung lining. Mice lacking CD97 exclusively in bronchial epithelial cells showed asthmatic responses comparable to control mice, while mice lacking CD97 specifically in leukocytes mirrored the full knockout phenotype. Levels of the epithelial alarmins TSLP and interleukin-33 remained equivalent across genotypes.
Dendritic cell regulation
Dendritic cells drove the exaggerated inflammatory response during early allergen sensitization. Applying a single dose of the CD97-blocking antibody 1B2 one day before house dust mite sensitization aggravated subsequent asthma in mice, whereas administering the antibody during the later allergen challenge produced no difference compared to control antibodies.
Lungs from allergen-sensitized mice lacking CD97 showed higher absolute numbers and frequencies of conventional type 2 dendritic cells and monocyte-derived dendritic cells. Bone marrow-derived dendritic cells deficient in CD97 expressed higher amounts of activation markers CD86 and CD80 when stimulated with allergens, lipopolysaccharide, or TNF. These knockout dendritic cells produced less interleukin-12, secreted more interleukin-1 beta or interleukin-6, and triggered stronger proliferation and interleukin-13 secretion when cultured with CD4-positive T cells.
Transferring allergen-pulsed CD97-deficient dendritic cells into naive recipient mice reproduced the exacerbated disease pattern. Recipient animals developed elevated eosinophil counts in bronchoalveolar lavage fluid, higher lung resistance, and increased type 2 cytokine output in mediastinal lymph nodes and spleen tissue.
Transcriptional changes and human data
RNA sequencing of allergen-pulsed bone marrow dendritic cells identified 153 genes with altered expression between normal and CD97-deficient cells. Functional analysis linked these differential genes to secretome shifts, extracellular space components, and cell communication pathways.
Single-cell transcriptomic profiles of lower-airway mucosal cells from human patients showed that mononuclear phagocytes, including conventional type 2 dendritic cells, express lower amounts of ADGRE5 following allergen challenge in allergic asthmatics compared to allergic non-asthmatics. In mice, the loss of CD97 was also accompanied by a higher frequency of GATA3-positive CD4 T cells in the lungs and draining lymph nodes within 24 to 72 hours after allergen exposure.
