Regulatory T-cells in asthma

Abstract

Purpose of review: This review addresses recent progress in our understanding of the role of regulatory T (Treg) cells in enforcing immune tolerance and tissue homeostasis in the lung at steady state and in directing the immune response in asthmatic lung inflammation.

Recent findings: Regulatory T cells regulate the innate and adaptive immune responses at steady state to enforce immune tolerance in lung tissues at steady state and their control of the allergic inflammatory responses induced by allergens. This regulatory function can break down in the context of chronic asthmatic airway inflammation such that the lung tissue Treg cells become skewed towards a pathogenic phenotype that aggravates and perpetuates disease. Subversion of lung tissue Treg cell function involves their upregulation of Notch4 expression, which in turn acts to amplify T helper type 2 and type 17 and innate lymphoid cell type 2 responses in the airways.

Summary: A dual role for Treg cells has emerged both as immune regulators but also a potential disease effectors in asthma, with implications for disease therapy.

Figure 1.

Regulatory T-cell function at steady state and in airway inflammation. In Steady state, Treg cells contribute to tissue repair via Amphiregulin, suppression of innate Immunity via miRNA or via Perforin and Granzyme A. Treg cell regulation takes place through cell-cell contact and by means of immune modulatory cytokines including IL-10, IL-35 and TGFβ. In airway inflammation, the function of Treg cells is redirected in favour of promoting a potentially host-protective inflammatory response. In chronic inflammation and especially in severe cases, Treg cells turn into proinflammatory phenotype and act in a positive feedback loop to aggravate the inflammatory responses.

Figure 2.

Role of Particulate Matter in augmentation of inflammatory responses in the lung. PM/UFP inhalation leads to activation of the aryl hydrocarbon receptor (AhR) in alveolar macrophages (AM) which in turn upregulates the expression of Jagged1 (Jag1) in AM (41). Jag1 along with IL-6 (and to a lesser extent IL-33) leads to the upregulation of Notch4 on Treg cells and the activation of downstream Hippo and Wnt pathway. Hippo pathway activation destabilizes the Treg cells towards a Th17 cell-like phenotype, while the Wnt pathway causes the Treg to acquire a Th2 cell-like phenotype (57). Production of Growth and Differentiation Factor 15 (GDF15) by Th2-like Treg cell leads in turn to upregulation of Innate Lymphoid Cells type 2 (ILC2) activity and higher production of IL-13. The IL-6-Notch4 circuit is amplified by the pro-asthmatic IL-4Rα-R576 variant to exacerbate allergic airway inflammation.