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.
Highlights
The three isoforms of transforming growth factor-b (TGF-b), TGF-b1, TGF-b2 and TGF-b3 in mouse and human, encoded by separate genes, are involved in a plethora of biological processes during development, lineage commitment, wound healing, proliferation, migration and survival of cells [1]
We restricted our analysis to the time period after the sensitization phase, to exclude the known effects of TGF-b signalling on T cell receptor signal strength during the priming phase of our experiment
Without induction of airway inflammation (AAI), induced T helper cells (Th) cell specific TGFb-receptor 2 (Tgfbr2) ablation did not result in any of the abovedescribed outcomes, highlighting the critical role of TGF-b signaling during the challenge phase of established AAI
Summary
The three isoforms of transforming growth factor-b (TGF-b), TGF-b1, TGF-b2 and TGF-b3 in mouse and human, encoded by separate genes, are involved in a plethora of biological processes during development, lineage commitment, wound healing, proliferation, migration and survival of cells [1]. TGF-b is known to be involved, and in some cases essential, for the development of regulatory T (Treg) cells, for differentiation and lineage commitment of Interleukin-17 producing T helper (Th17) cells (mouse only), of follicular T helper (Tfh) cells (human only) and of IL-9 producing T helper (Th9) cells [8, 9]. The various outcomes of TGF-b signaling are achieved through combinatorial sensing of additional cytokines (such as IL-6, IL-1, IL21 in combination with TGF-b for Th17 induction), result from specific local cytokine milieus [14]
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