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

Allergic airway inflammation involves complex neuro‑immune interactions, yet the role of α2A‑adrenergic receptors (α2AR, encoded by Adra2a) in Tfh development and type 2 immunity remains poorly defined. HDM‑induced asthma model was established in C57BL/6 mice. RNA‑sequencing, correlation analysis, flowcytometry, immunofluorescence, and pharmacological interventions were used. Il33 knockout mice and T‑cell‑specific Adra2a or Akt1 knockout mice were generated. GEO datasets were analyzed for Tfh cell signatures. We found that HDM challenge significantly upregulated Adra2a in lung and lymph nodes. Adra2a expression was strongly correlated with type 2 chemokines Ccl11, Il33, and Ccl17. In Il33KO mice, Adra2a was among the top downregulated genes, and Il33 deletion broadly suppressed type 2 inflammation genes. Catecholamine‑metabolizing enzymes showed differential correlations: Maoa positively correlated with Adra2a and asthma genes, whereas Maob and Ddc were negatively correlated. α2AR was highly expressed on Tfh cells, especially on GC‑Tfh cells. α2AR activation aggravated airway inflammation, increased Tfh and germinal center B cells, promoted type 2 cytokines and IgE, and AKT phosphorylation. Conversely, T‑cell‑specific Adra2a knockout or Akt1 knockout attenuated these effects. α2AR is a key regulator linking neuro‑immune crosstalk to type 2 airway inflammation. It promotes Tfh cell differentiation and allergic responses via AKT signaling. Targeting α2AR may represent a novel therapeutic strategy for asthma. In a house dust mite (HDM)-induced mouse model of asthma, HDM challenge leads to upregulation and activation of the α2AR adrenergic receptor, subsequently promoting Tfh differentiation and allergic responses via AKT signaling. These results suggest that targeting α2AR may represent a future therapeutic strategy for asthma. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give... [797 chars]