Type-2 CD8+ T lymphocytes responsive to PGD2/LTE4 in severe eosinophilic asthma

Abstract

Background: Severe asthma with persistent airway eosinophilia despite high-intensity inhaled corticosteroids is a phenotype associated with high exacerbation risk. A major barrier to progress is poor understanding of the pathogenic mechanisms and cell types contributing to the disease. Aims and objectives: To determine the function of type-2 cytokine producing CD8+ T cells in severe eosinophilic asthma, and investigate their contribution to pathogenesis of the disease. Methods: Profiles of type-2 CD8+ T cells (Tc2) and type-2 T helper (Th2), in different asthma phenotypes were analysed with flow cytometry. Tc2 cells were isolated and cultured in vitro. Effects of prostaglandin D2 (PGD2) and leukotriene E4 (LTE4) on Tc2 cells were defined using chemotaxis assays, Luminex, quantitative RT-PCR, PrimeFlow RNA assay and microarray. Effects of Tc2 supernatants were determined on eosinophil shape change and apoptosis, and on eosinophil chemokine production from airway epithelial cells. Results: In two independent patient cohorts we show that, in contrast to Th2 cells, type-2 cytokine-secreting CD8+CRTH2+ Tc2 cells are enriched in blood and airways, and concentrations of prostaglandin D2 (PGD2) and cysteinyl leukotriene E4 (LTE4) are also increased in the airways in severe eosinophilic asthma. In vitro PGD2 and LTE4 function synergistically to enhance Tc2 cell recruitment and activation. They regulate diverse genes in Tc2 cells inducing type-2 cytokines and many other pro-inflammatory cytokines and chemokines which could contribute to eosinophilia. Conclusions: These finding are consistent with an important role for human Tc2 cells in severe eosinophilic asthma.