Abstract
Human type-2 CD8+ T cells are a cell population with potentially important roles in allergic disease. We investigated this in the context of severe asthma with persistent airway eosinophilia—a phenotype associated with high exacerbation risk and responsiveness to type-2 cytokine-targeted therapies. In two independent cohorts we show that, in contrast to Th2 cells, type-2 cytokine-secreting CD8+CRTH2+ (Tc2) cells are enriched in blood and airways in severe eosinophilic asthma. Concentrations of prostaglandin D2 (PGD2) and cysteinyl leukotriene E4 (LTE4) are also increased in the airways of the same group of patients. In vitro PGD2 and LTE4 function synergistically to trigger Tc2 cell recruitment and activation in a TCR-independent manner. These lipids regulate diverse genes in Tc2 cells inducing type-2 cytokines and many other pro-inflammatory cytokines and chemokines, which could contribute to eosinophilia. These findings are consistent with an important innate-like role for human Tc2 cells in severe eosinophilic asthma and suggest a potential target for therapeutic intervention in this and other diseases.
Highlights
Type-2 cytokines (interleukin (IL)-4/5/9/13) orchestrate allergic inflammation, driving type-2 CD4+ T helper (Th2) cell differentiation, IgE production, mucus hypersecretion and airway hyperresponsiveness (AHR)
type-2 cytokine-secreting CD8+CRTH2+ (Tc2) cells are enriched in eosinophilic asthma CRTH2 is highly expressed on type-2 cytokine-producing human peripheral blood CD8+ T lymphocytes
CRTH2 and CysLT1 in individual Tc2 cells were paired compared between healthy controls and severe asthma groups with flow cytometry. b Levels of prostaglandin D2 (PGD2) and leukotriene E4 (LTE4) in sputum determined with enyme-linked immunosorbent assay (ELISA) were compared between healthy controls and severe asthma groups. *p < 0.05 (Supplementary Fig. 1a).[22]
Summary
Type-2 cytokines (interleukin (IL)-4/5/9/13) orchestrate allergic inflammation, driving type-2 CD4+ T helper (Th2) cell differentiation, IgE production, mucus hypersecretion and airway hyperresponsiveness (AHR). Cell populations exist, their overall functionality, transcriptional machinery and the mechanisms by which they are triggered have not been defined This is important to address as recent data in other contexts have revealed previously overlooked functional diversity of human CD8+ T cells in inflammatory diseases.[5]. Our observations provide compelling evidence of innate-like activation of Tc2 cells by pro-inflammatory lipids, a diverse range of functions of this cell population, and a potential role in severe eosinophilic asthma
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