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

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.

Insights into the epigenetics of chronic rhinosinusitis with and without nasal polyps: a systematic review

“…In addition, it can regulate cell proliferation, differentiation, and growth; immune function; and expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. It promotes either T-helper 17 cells (Th17) or regulatory T cells (Treg) lineage differentiation in a concentration-dependent manner (87).…”

“…The role of TGF beta-1 has been extensively investigated in asthma (87)(88)(89)(90). In addition, its role as a biomarker in diagnosing severe asthma has also been investigated (91).…”

Immune checkpoint molecules in prevention and development of asthma

“…The release of alarmins promotes the stimulation of Th2 cells, type 2 innate lymphoid cells (ILC2s), and other immune cells such as macrophages, basophils and eosinophils (4). However, investigations reveal that other cytokines such as TGF-b1, which is involved in tissue remodeling during airway inflammation, also contributes to the pathogenesis of asthma through induction of Th2 and Th9 and suppression of Treg cells (5). In contrast, IL-37 down-regulates asthmatic airway inflammation by counterbalancing the disease-amplifying effects of IL-1b and IL-33 (6).…”

T-helper cells and their cytokines in pathogenesis and treatment of asthma

“…IL-9 promotes the pathogenesis of asthma by activating and recruiting mast cells and eosinophils, enhancing B-cell IgE production, increasing epithelial cell mucus production, and triggering airway AHR (29,61). Natural allergen exposure raised local and systemic Th2, Th9, and reduced Tregs cells, but allergen-specific immunotherapy(AIT) inhibited Th2 and Th9 cell frequencies along with transforming growth factor (TGF)-b and IL-9 secretion (62). A crucial proinflammatory mediator in allergy reactions, activin A, a TGFsuperfamily member connected to TGF-b1, also regulates Th9 development and effector activities (63).…”

“…A crucial proinflammatory mediator in allergy reactions, activin A, a TGFsuperfamily member connected to TGF-b1, also regulates Th9 development and effector activities (63). Musiol et al found that targeting the TGF-b pathway may not only inhibit airway remodeling processes but also target pro-inflammatory Th2 and Th9 cells without adversely affecting immune tolerance in the asthmatic model (62). Another study found that activin-A was able to replicate the ability of TGF-b1 to drive Th9 polarization in vitro and in vivo.…”