TGF-β1 Drives Inflammatory Th Cell But Not Treg Cell Compartment Upon Allergen Exposure

Abstract

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 and Th17 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 is a major player in AAI by driving effector T cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the gene encoding for TGFβ-receptor 2 (Tgfbr2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of pro-inflammatory T cell frequencies (Th2, Th9, Th17), but increased Treg cells. To translate these findings into a human clinically relevant context, Th2, 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, and reduced Tregs cells, 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 cells.

Distinct spatial and temporal roles for Th1, Th2, and Th17 cells in asthma

“…TGF-b, a pleiotropic cytokine, has been reported to be constitutively produced by alveolar macrophages (44). In the context of allergic airway inflammation, it is important to note that TGF-b1 drives the Th9 and Th17 cell differentiation while the differentiation of Treg cell is independent of TGF-b1 (45). Exposure to air pollution, especially particulate matter less than 2.5mm that easily reaches small airways and alveoli, via interacting aryl hydrocarbon receptor, promotes Th17 cell differentiation to aggravate asthma (46).…”

Allergen-specific immunotherapy with Alutard SQ improves allergic inflammation in house-dust mites-induced allergic asthma rats through inactivation of the HMGB1/TLR4/NF-κB pathway

“…AIT increases secretoglobin 1A1 expression in cells of the lower airways from patients with allergic asthma to improve airway inflammatory response ( 34 ). It also suppresses TGF-β1 in asthma airway epithelial cells, which regulate airway inflammation and remodeling in asthma due to its anti-inflammatory and profibrotic effect ( 35 , 36 ). Similarly, our study showed that Alutard SQ inhibited the HDM-induced TGF-β1 protein secretion, and airway inflammation.…”

A role for age-associated alterations in esophageal epithelium in eosinophilic esophagitis-associated fibrosis

“…Indeed, soluble factors from inflammatory cells, including eosinophil-generated TGF-β and IL-1β ( 8 ), and endothelial cell-derived TSPAN12 ( 54 ) have been implicated in EoE fibrosis. TGF-β has also been demonstrated to promote induction of effector T cells but not regulatory T cells in the context of allergic airway inflammation ( 55 ), highlighting the importance of crosstalk with the immune system in allergic inflammation. EoE inflammation may also impact molecular tissue age as suggested by a recent study that reported evidence of epigenetic events associated with premature molecular aging in esophageal biopsies from EoE patients but not those from normal controls ( 56 ).…”