TGF-β1 drives Th9 but not Treg cells upon allergen exposure

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β acts in AAI by driving effector T cells into Th9 cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the TGFβ-receptor 2 (TGFBR2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of Th9 cell frequencies, but increased Treg cells. To translate these findings into a human clinically relevant context, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9 cell and reduced Tregs, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs. ### Competing Interest Statement Dr. Chaker reports grants for clinical studies and research and other from Allergopharma, ALK Abello, AstraZeneca, Bencard / Allergen Therapeutics, ASIT Biotech, Immunotek, Lofarma, GSK, Novartis, LETI, Roche, Sanofi Genzyme and Zeller. Prof. Schmidt-Weber reports speaker fees from Bencard, personal fees from Allergopharma, during the conduct of the study. * AA : allergic asthma AAI : allergic airway inflammation AHR : airway hyperreactivity AIT : allergen-specific immunotherapy AR : allergic rhinitis BAL : Bronchoalveolar lavage BALF : Bronchoalveolar lavage fluid ICI : Inflammatory cell infiltrate i.p. : intraperitoneal Mch : metacholin n.d. : not detectable OVA : ovalbumin PBMC : peripheral blood mononuclear cell PBS : Phosphate-buffered saline mRQLQ : Rhinoconjunctivitis Quality of Life mini Questionnaire tIgE : total Immunoglobulin E Tregs : regulatory T cells Th : T helper cells