T cells in severe childhood asthma

Abstract

Severe asthma in children is a debilitating condition that accounts for a disproportionately large health and economic burden of asthma. Reasons for the lack of a response to standard anti-inflammatory therapies remain enigmatic. Work in the last decade has shed new light on the heterogeneous nature of asthma, and the varied immunopathologies of severe disease, which are leading to new treatment approaches for the individual patient. However, most studies to date that explored the immune landscape of the inflamed lower airways have focused on adults. T cells are pivotal to the inception and persistence of inflammatory processes in the diseased lungs, despite a contemporary shift in focus to immune events at the epithelial barrier. This article outlines current knowledge on the types of T cells and related cell types that are implicated in severe asthma. The potential for environmental exposures and other inflammatory cues to condition the immune environment of the lung in early life to favour pathogenic T cells and steroid resistance is discussed. The contributions of T cells and their cytokines to inflammatory processes and treatment resistance are also considered, with an emphasis on new observations in children that argue against conventional type 1 and type 2 T cell paradigms. Finally, the ability for new technologies to revolutionize our understanding of T cells in severe childhood asthma, and to guide future treatment strategies that could mitigate this disease, is highlighted.

Figure 1.. Theoretical Model of T-Cell Circuits in Asthma.

In asthma, dendritic cells proximal to the epithelial barrier are coordinately primed by exposure to a variety of antigens and cytokines produced by epithelial cells. This results in their maturation and migration to regional lymph nodes where they engage naive T cells, resulting in Th differentiation. These effector cells are armed to traffic to the respiratory tract where they exit the circulation and exert their effector function by releasing characteristic cytokines. The T-cell landscape in children with severe asthma is “mixed”, and there is likely a complex interplay between different Th types.

Figure 2.. Mechanisms that Condition the Lung’s Immune System for Asthma.

Innate lymphoid cells bridge innate and adaptive responses, and are likely to be integral to T-cell outcomes in asthma. The figure summarizes concepts derived from mouse models of asthma, including early life models, and from in vitro systems. Theoretical links to specific Th subsets that have been implicated in severe asthma of childhood are depicted.

Figure 3.. New and Emerging Treatments for Severe Asthma.

Drugs that exert a potential T-cell-modulatory effect are depicted. Each drug and its corresponding target molecule(s)/ pathway(s) is colored accordingly. Some drugs have the potential to impact both type 2 responses and type 1/type 17 responses, for example, by acting on T cells that co-express IL-4 and IL-17 (brodalumab), or by blocking the inhibitory role of IgE on IFN-α production in pDC (omalizumab). Although some treatments have been shown to reduce blood/sputum eosinophils, the effects on T cells remain unknown.