Investigation of a novel subset of TNFR2 expressing regulatory T cell in lung diseases

The immune system in the lung employs various mechanisms to maintain and restore lung homeostasis and protect the host against exacerbated responses to various environmental stimuli. The existence of CD3+CD4+CD25+ regulatory T cells (Treg) that actively suppress the function of T effector cells (Teff) is a key mechanism by which the immune system limits inappropriate or excessive inflammatory responses. In acute and chronic airway inflammation (e.g. allergen induced airway inflammation), Teff secreted various pro-inflammatory cytokines including activin A, TGF-b, IL-4, IL-5 and IL-13 that skew immune response towards T helper 2 cells (Th2). Lung exposure to cytokine antagonist (e.g. biological factors such as follistatin that bind activin A) decreased lung inflammatory responses with an increase in Treg, reflecting the therapeutics effects of targeting pro-inflammatory cytokines. In acute lung injury [e.g. lipopolysaccharides (LPS)-induce acute lung injury], the immune response was skewed towards Th17 cells that secreted higher levels of IL-17 together with other pro-inflammatory cytokines such as TNF, IL-10 and IL-6. Excessive pro-inflammatory cytokines secreted in the lung modify lung equilibrium of Teff and Treg altering their characteristics (e.g. proliferative capacity and function) in that microenvironment. An imbalance in Treg/Teff ratios led to the induction of acute inflammatory responses (e.g. lung injury or allergic airway inflammation) that fully resolved a month after exposure to stimuli. After the inflammation resolved, Treg/Teff ratios returned to homeostatic levels. Lung exposure to inert engineered materials [polystyrene 50 nm nanoparticles (PS50G)] did not only induce lung immune activation, however it also pre-conditioned for an increase in the frequency and the suppressive capacity of lung TNFR2 expressing Treg (i.e. increased the levels of suppressor molecules). Experimental data suggests that lung exposure to bacterial products (e.g. LPS) and PS50G protects individuals from developing allergic airway inflammation. PS50G facilitated an increase in the quantity and quality of lung TNFR2 expressing Treg which were perfectly positioned to respond rapidly to allergenic challenges and restored lung immune homeostasis. Therefore, targeting highly bioactive TNFR2 expressing Treg poses a new therapeutic avenue to promote healthy lung homeostasis. Overall, the novel findings of the effects of follistatin, LPS and engineered PS50G on TNFR2 expressing Treg may increase the chances that these stimuli will translate to new generic treatment for lung inflammation, particularly allergic diseases.