Synergistic activation of pro-inflammatory type-2 CD8⁺ T lymphocytes by lipid mediators in severe eosinophilic asthma

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.