CD8+ Tc2 cells: underappreciated contributors to severe asthma

Abstract

The complexity of asthma is underscored by the number of cell types and mediators implicated in the pathogenesis of this heterogeneous syndrome. Type 2 CD4⁺ T-cells (Th2) and more recently, type 2 innate lymphoid cells dominate current descriptions of asthma pathogenesis. However, another important source of these type 2 cytokines, especially interleukin (IL)-5 and IL-13, are CD8⁺ T-cells, which are increasingly proposed to play an important role in asthma pathogenesis, because they are abundant and are comparatively insensitive to corticosteroids. Many common triggers of asthma exacerbations are mediated via corticosteroid-resistant pathways involving neutrophils and CD8⁺ T-cells. Extensive murine data reveal the plasticity of CD8⁺ T-cells and their capacity to enhance airway inflammation and airway dysfunction. In humans, Tc2 cells are predominant in fatal asthma, while in stable state, severe eosinophilic asthma is associated with greater numbers of Tc2 than Th2 cells in blood, bronchoalveolar lavage fluid and bronchial biopsies. Tc2 cells strongly express CRTH2, the receptor for prostaglandin D2, the cysteinyl leukotriene receptor 1 and the leukotriene B4 receptor. When activated, these elicit Tc2 cell chemotaxis and production of chemokines and type 2 and other cytokines, resulting directly or indirectly in eosinophil recruitment and survival. These factors position CD8⁺ Tc2 cells as important and underappreciated effector cells contributing to asthma pathogenesis. Here, we review recent advances and new insights in understanding the pro-asthmatic functions of CD8⁺ T-cells in eosinophilic asthma, especially corticosteroid-resistant asthma, and the molecular mechanisms underlying their pathologic effector function.

FIGURE 1

Under the influence of interleukin-(IL)-4, type 2 CD8⁺ (Tc2) cells differentiate from naïve CD8⁺ T-cells or arise by transcriptional reprograming of Tc1 cells. Tc2 cells highly express chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), a receptor for prostaglandin D2 (PGD₂). In addition, Tc2 cells express the cysteinyl leukotriene receptor 1 (CysLT₁) and leukotriene B4 receptor (BLT-1). Inflammatory stimuli, such as cross-linking of immunoglobulin (Ig)E on mast cells, leads to production of eicosanoids. Through CRTH2, PGD₂ elicits Tc2 cell chemotaxis, activation and production of chemokines, type 2 cytokines and other cytokines, resulting directly or indirectly in eosinophil recruitment and survival. In turn, airway eosinophilia is associated with airway remodelling and exacerbations. ATF2: activating transcription factor-2; CCL: C-C motif chemokine ligand; GM-CSF: granulocyte–macrophage colony-stimulating factor; LT: leukotriene; MKP: mitogen-activated protein kinase phosphatase; Th2 cells: type 2 CD4⁺ T-cells; TNF: tumour necrosis factor.

FIGURE 2

Tc2 cells are enriched in eosinophilic asthma. a) Frequencies of CD3⁺CD8⁺CRTH2⁺ Tc2 and CD3⁺CD4⁺CRTH2⁺ Th2 cells in CD4⁺ or CD8⁺ T-cells in total peripheral blood leucocytes compared between healthy controls and severe asthma patient groups (eosinophilic and non-eosinophilic) in a cohort from Oxford, UK by flow cytometry. b,c) Tc2 cells are increased in lung in eosinophilic asthma in a cohort from Southampton, UK. Frequencies of CD3⁺CD8⁺IL-13⁺ and CD3⁺CD4⁺IL-13⁺ T-cells in b) bronchial biopsy and c) bronchoalveolar lavage (BAL) compared between healthy controls and asthma groups (eosinophilic and non-eosinophilic) by intracellular cytokine staining. *: p<0.05, ***: p<0.001. Reproduced and modified from [88] with permission.