Epidermal growth factor receptor (EGFR) acts as a critical switch amplifying type‑2 (T2) immune responses in female lungs, potentially explaining why adult women often experience more severe asthma than men. That discovery comes from new mouse and human cell data reported in the paper, “Epidermal Growth Factor Receptor Controls Sex Differences in Lung Type 2 Responses to Inhaled Allergen.” The study’s findings were published in Science Immunology.
In experiments centered on house‑dust‑mite (HDM) allergen, British researchers found that female mice mounted stronger T2 responses than males — a sex gap that disappeared when EGFR signaling was blocked. The study also ties estrogen and the alarmin IL‑33 to EGFR activity, outlining a hormonal pathway that could guide future therapies.
In their study, researchers exposed male and female mice to intermittent HDM from postnatal day seven through six weeks of age — a window spanning major hormonal changes — to track sex‑specific lung immunity. They then inhibited EGFR with gefitinib after weaning to test whether the receptor drives the observed differences. Across 125 measured variables, HDM‑exposed females showed higher IL‑33 in lungs and elevated T2 signatures — IL‑5, IL‑13, IL‑10‑producing CD4 T cells, BAL IL‑13, total serum IgE and expression of T2‑linked genes — compared with males. These differences vanished under EGFR blockade, implicating EGFR in the female‑skewed response.
Additionally, researchers found that giving IL‑33 to sensitized male mice boosted T2 immunity and upregulated EGFR on TH2 cells. In vitro, EGFR inhibition suppressed T2 cytokine production. In vivo, EGFR inhibition reduced T2 immunity only in females, erasing the sex gap. Separately, dosing males with E2 elevated lung IL-33 and T2 responses to levels seen in females, suggested an E2 to IL-33 to EGFR cascade. IL‑33 directly induced IL‑5 and IL‑13 release from in vivo‑polarized TH2 cells and increased EGFR expression on CD4 T cells. EGFR signaling was required for TH2 cytokine secretion in response to either IL‑33 or HDM antigen.
According to the study’s authors, asthma prevalence and severity tends to be higher in women after puberty, with symptom swings during hormonal transitions such as menstrual cycles, pregnancy and menopause. They noted that this study strengthens a long‑suspected connection between female hormones and heightened T2 inflammation by pinpointing a molecular axis — E2 to IL to 33 to EGFR — that amplifies allergen‑driven TH2 activity in female lungs.
Although EGFR inhibitors like gefitinib are approved in oncology, their pulmonary side effects — including interstitial lung disease — and poor tolerability when inhaled make them risky candidates for chronic asthma, researchers noted. By contrast, IL‑33‑targeting biologics (e.g., itepekimab) have shown good tolerability and some efficacy on lung function and asthma control in early clinical trials. The authors suggest that a temporally targeted IL‑33 blockade could offer a pragmatic route for women with exacerbated T2 immunity or those undergoing hormonal fluctuations, potentially blunting the EGFR‑dependent amplification without EGFR’s toxicity baggage.
Prior research linked IL‑33 to EGFR indirectly through the EGFR ligand amphiregulin and to general tissue repair pathways. This new study, the authors said, extends that relationship by showing IL‑33 directly increases EGFR on TH2 cells and that EGFR signaling is a requirement for T2 cytokine release, placing EGFR at the heart of adaptive T2 amplification rather than only epithelial repair. It also frames a plausible feedback loop: IL‑33 elevates EGFR and drives intracellular ST2 dynamics on CD4 T cells, sustaining IL‑5/IL‑13 production and airway inflammation.
Researchers did caution that early‑life mouse models mirror several clinical features — airway hyperresponsiveness, epithelial injury, T2 signatures — but neonatal hormone manipulations are technically constrained, and serum hormone measurements hover near assay detection limits. As a result, definitive assignment of each step to T2 signaling in specific lung cell types awaits genetic models.
Ultimately, researchers said they believe the study offers new hope by connecting estrogen, IL‑33 and EGFR, giving way to a sex‑informed strategy to temper T2 flares during periods of hormonal flux.
