Chimeric allergen receptor regulatory T cells suppress birch pollen allergic airway inflammation

Asthma is a deadly chronic respiratory disease affecting over 300 million people. While allergen immunotherapy remains the only disease-modifying treatment, it is poorly applicable for patients with severe asthma. Here, we explored the therapeutic potential of regulatory T cells (Tregs) armed with chimeric allergen receptors-named CAlleR-redirected against the major allergen of birch pollen Bet v1. Four novel anti-Bet v1 antibodies were identified and used to engineer and functionally validate CAlleR. CAlleR Tregs showed specific in vitro activation and suppression and significantly reduced the airway hyperresponsiveness in birch pollen-sensitized mice. Mechanistically, CAlleR Tregs migrated to the lungs and mediastinal lymph nodes, interacted with CD11c+ dendritic cells, and were activated in a FcγR-dependent manner by cross-presenting Bet v1 stabilized with noncompetitive anti-Bet v1 antibodies. These findings unveil a novel mechanism for targeting soluble antigens and highlight the potential of CAlleR Tregs to prevent and treat severe allergies.