The α2A-adrenergic receptor on Tfh cells amplifies allergic airway inflammation via Akt signaling

Bronchial asthma is a prevalent chronic inflammatory disease characterized by aberrant immune regulation. While β2-adrenergic signaling has been extensively studied in asthma, the role of other adrenergic receptors remains unclear. Here, we identify α2A-adrenergic receptor (α2AR, coded by Adra2a ) as a key modulator of allergic airway inflammation. Transcriptomic analysis of house dust mite (HDM)-induced asthmatic mice revealed significant upregulation of Adra2a , which correlated with increased catecholamine metabolism and type 2 inflammation. α2AR was predominantly expressed on follicular helper T (Tfh) cells in germinal centers. Pharmacologic activation of α2AR enhanced Tfh cell differentiation, GC B cell responses, and Akt-S473 phosphorylation, exacerbating asthma severity. Conversely, Adra2a deletion in CD4 T cells or inhibition by BRL-44408 reduced Tfh and GC B cell frequencies, serum IgE, and airway inflammation. CD4 T cell-specific Akt1 knockout mice showed similar reduction in Tfh responses and GC activity. These findings identify α2AR as a novel neuroimmune regulator that amplifies Tfh-GC B axis–driven airway inflammation through Akt signaling, offering a potential therapeutic target for asthma.