Natural killer T-cells in asthma pathogenesis and treatment: old problems and future perspectives

Abstract

Natural killer T-cells (NKT-cells) are immunological cells expressing features of both innate and adaptive immunity, which have been reported to be involved in the pathogenesis of asthma and in the induction of airway hyperresponsiveness (AHR). In this review we discuss the controversial results obtained in the past due to the lack of standardised analytical methods and the inhomogeneity of cohorts. In recent years, the availability of more advanced techniques led to a significant improvement in the phenotyping of these cells. Several research studies, both in mice and humans, reported that NKT-cells might be involved in the induction of AHR through the secretion of cytokines. In mouse models, in the absence of NKT-cells, AHR was not triggered and the airway eosinophil count was reduced. A relationship between NKT-cells and both innate (e.g. dendritic cells) and adaptive cells (e.g. Tregs) was demonstrated as well. These cells are seemingly able to produce different sets of cytokines, depending on their micro-environment. Moreover, numbers of NKT-cells derived from bronchoalveolar lavage were higher compared to those from peripheral blood samples. Lastly, the possibility to administer novel monoclonal antibodies against several interleukin (IL) pathways (such as anti-IL-5 and anti-IL-13, which can both be secreted by NKT-cells) further places these cells at the core of the pathogenesis of asthma and highlights the need for further discussion.

FIGURE 1

Comparison between the three main types of NKT-cell classifications: TCR-based classification, divided into Type 1 NKT-like cells, also known as iNKT, and Type 2; surface markers CD4 and CD8 classification; effector function classification, which involves only iNKT-like cells and is based on transcription factors. NKT-cell: natural killer T-cell; iNKT-cell: invariant NKT-like cells; Th: T-helper; Treg: T regulatory cell.

FIGURE 2

Interactions between NKT-cells and other immunological cells. This picture summarises the types of interaction carried out by iNKT-cells and other immunological cells. Lower left side: iNKT-cells express the CD40 ligand (CD40L) which binds to the CD40 receptor (CD40R) expressed on lung dendritic cells (LDC); this interaction causes the increased expression of MHC-II, CD80 and CD86, which represent surface maturation markers of LDC cells. The interaction also induces the release of proinflammatory cytokines. Top: allergens and pollutants in asthma models induce the release of several types of cytokines and interleukins (IL). iNKT-cells express the TSLP receptor, which when activated by its ligand induces the production of IL-13, which can directly induce airway hyperreactivity (AHR) and bronchoconstriction. Lower right side: Treg cells can regulate the migration of iNKT-cells through CD39 thus reducing their concentration in the lungs, whereas antiCD25 reverses the effect. iNKT-cell: invariant natural killer; NKT-cell: natural killer T-cell; Treg: T regulatory cell; TSLP: thymic stromal lymphopoietin; TNF-α: tumour necrosis factor α; MHC: major histocompatibility complex.

FIGURE 3

Two pathways of activation of iNKT-cells: through CD1d (on the left) and through CCR9 and CCL25 (on the right), with consequential production of IL-4 and IL-13. Conventional CD3⁺ αβ T-cells can be polarised to a Th2 phenotype by cell-to-cell contact with Vα24⁺ iNKT-cells, with subsequent enhanced expression of CCR9. This induction requires CCL25 and CCR9 to activate adjacent membrane signalling by CD226. iNKT-cell: invariant natural killer T-cell; DC: dendritic cell.