Regulatory T cells in asthma

Abstract

Asthma is characterized by T helper cell 2 (Th2) type inflammation, leading to airway hyperresponsiveness and tissue remodeling. Th2 cell-driven inflammation is likely to represent an abnormal response to harmless airborne particles. These reactions are normally suppressed by regulatory T cells, which maintain airway tolerance. The anti-inflammatory cytokine IL-10 is likely to play a central role. The role of the cytokine transforming growth factor beta (TGF-beta) is more complex, with evidence for immune suppression and remodeling in the airways. In asthmatic individuals there is a breakdown in these regulatory mechanisms. There is emerging evidence that early life events, including exposure to allergen and infections, are critical in programming effective regulatory pathways to maintain pulmonary homeostasis. In this review we examine the clinical and experimental evidence for T regulatory cell function in the lung and discuss the events that might influence the functioning of these cells. Ultimately, the ability to enhance regulatory function in affected individuals may represent an effective treatment for asthma.

Figure 1. Regulatory Pathways Maintain Lung Homeostasis

The lung is maintained in a state of homeostasis by a complex network of cells and molecules. IL-10 plays a central role in this process, but the role of TGF-β is less clear at present. Exposure of susceptible individuals to allergen is associated with a Th2 cell type immune response characterized by IL-4, IL-5, IL-13, and TNF, which culminates in leukocyte infiltration of the lungs. The development of this inflammation is influenced by multiple factors, but early childhood infection, diet, vitamin D, and TLR ligand expression all affect the initiation and development of the allergic response. In a proportion of individuals, inflammation is chronic and associated with significant remodeling of the airways. IL-10 and TGF-β are thought to be able to promote resolution of inflammation whereas TFG-β family members initiate tissue repair and remodeling. Induction of TGF-β by Th2 cytokines during acute inflammation may also contribute to lung remodeling. Whether chronic asthma develops as a result of ineffective inflammatory resolution or as an aberrant wound healing response is the subject of investigation, but it is likely that IL-10 and TGF-β are key mediators.

Figure 2. Effect of Current Asthma Treatments on Regulatory Pathways

Regulatory T cells inhibit effector T cells, antigen-presenting cells, and cells of the innate immune response associated with the asthmatic reaction. Corticosteroids, a key treatment for asthma, are associated with the upregulation of both Foxp3⁺ Treg cells and IL-10 production by CD4⁺ T cells. Allergen immunotherapy has also been associated with an increase in allergen-specific IL-10-secreting Treg cells. More recent data suggest that Foxp3⁺ Treg cells may also be increased by this treatment. Vitamin D may both directly increase IL-10 and also enhance steroid-induced IL-10 production. Both Foxp3⁺ and IL-10⁺ (Foxp3-negative and -positive) Treg cell populations are likely to use additional inhibitory mechanisms including cell-contact-dependent pathways and cytotoxicity.