Functions of T cells in asthma: more than just T(H)2 cells

Abstract

Asthma has been considered a T helper 2 (T(H)2) cell-associated inflammatory disease, and T(H)2-type cytokines, such as interleukin-4 (IL-4), IL-5 and IL-13, are thought to drive the disease pathology in patients. Although atopic asthma has a substantial T(H)2 cell component, the disease is notoriously heterogeneous, and recent evidence has suggested that other T cells also contribute to the development of asthma. Here, we discuss the roles of different T cell subsets in the allergic lung, consider how each subset can contribute to the development of allergic pathology and evaluate how we might manipulate these cells for new asthma therapies.

Trial registration: ClinicalTrials.gov NCT00707811 NCT00712205 NCT00968669.

Figure 1. T cells involved in the induction of the allergic phenotype

Asthma is a heterogeneous disease that is characterized by airway hyperresponsiveness (AHR), recruitment of inflammatory leukocytes to the lung and tissue remodelling, including mucus production and airway smooth muscle changes. A number of different T cell subsets are thought to influence the nature and magnitude of the allergic immune response by the cytokines that they secrete. T helper 2 (T_H2) cells are thought to promote eosinophil recruitment, in conjunction with nature killer T (NKT) cells and CD8⁺ T cells. By contrast, T_H1 cells and T_H17 cells are thought to be associated with severe, steroid-resistant asthma, which is often marked by neutrophilic infiltrates. Regulatory T (T_Reg) cells and subtypes of γδ T cells are able to downregulate pulmonary immune responses and are thought to be important for maintenance of immune homeostasis in the lungs. The nature and magnitude of allergic inflammation in the lung is influenced by external environmental stimuli, such as exposure to allergens and pollution as well as infection with pathogens. IFNγ, interferon-γ; IL, interleukin.

Figure 2. Alternative pathway to a T_H2-type response in the airways

Cysteine protease activity and endotoxin within allergens can activate lung epithelial cells through protease-activated receptors (PARs) and pattern-recognition receptors (PRRs), such as Toll-like receptors. Recent experimental data indicate that a population of ‘innate helper’ cells can secrete interleukin-4 (IL-4) and IL-13 in response to epithelial cell-derived cytokines, such as IL-33 and IL-25, and promote T helper 2 (T_H2)-type immune responses. Thymic stromal lymphopoietin (TSLP) can promote T_H2-type responses in the lung, but a direct association with this cytokine and innate helper cells in the lung has not yet been found. Although these innate helper cells have been identified in a number of different tissues, including in the resting lungs, evidence for their involvement in allergic airway inflammation remains indirect. Therefore the model described here is theoretical and remains to be tested in vivo.

Figure 3. T cell subset signatures are affected by a variety of genetic and environmental influences

T cell subsets can be distinguished by their cytokine secretion patterns, as well as by their chemokine receptor expression. Distinct T cell lineages are determined by the expression of ‘master’ transcription factors. Although once thought to be committed stable lineages, it is becoming apparent that a range of environmental and genetic influences are able to promote flexibility in T cell programmes. Thus, effector subsets can rapidly react to changing environmental circumstances to promote effective immune responses. CCR, CC-chemokine receptor; CXCR, CXC-chemokine receptor; FOXP3, forkhead box P3; GATA3, GATA-binding protein 3; IFNγ, interferon-γ; IL, interleukin; RORγt, retinoic acid receptor-related orphan receptor-γt; STAT, signal transducer and activator of transcription; T_H, T helper; T_Reg, regulatory T.