Abstract
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.
Footnotes
Conflict of interest U.M.Z. received payment for manuscripts from Deutsches Aerzteblatt and funds for travel from the European Academy of Allergy and Clinical Immunology (EAACI) and Collegium Internationale Allergologicum (CIA). C.B.S.-W. received support for research projects from PLS Design, LETI, Zeller AG, and Allergopharma and accepted honoraria for consultancy and seminars from LETI and Allergopharma. He also received travel support from EAACI. A.M.C. has consultant arrangements through Technical University Munich with Allergopharma, ALK-Abello, HAL Allergy, Mundipharma, and Lofarma; has conducted clinical studies and received research grants through Technical University Munich from Allergopharma, Novartis, the German Federal Environmental Agency, Bencard/Allergen Therapeutics, ASIT Biotech, and Zeller AG; has received payment for lectures from Allergopharma, ALK-Abello, and GlaxoSmithKline; has received payment for manuscript preparation from Bayerisches Aerzteblatt; and has received travel support from the European Academy of Allergy and Clinical Immunology (EAACI), DGAKI, and SMI. The rest of the authors declare that they have no relevant conflicts of interest.
Abbreviations
- 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