CD8+ TEMRAs in Severe Asthma Associate with Asthma Symptom Duration and Escape Proliferation Arrest.

Aberrant immune response is a hallmark of asthma, with 5-10% of patients suffering from severe disease exhibiting poor response to standard treatment. A better understanding of the immune responses contributing to disease heterogeneity is critical for improving asthma management. T cells are major players in the orchestration of asthma, in both mild and severe disease, but it is unclear whether specific T cell subsets influence asthma symptom duration. Here we show a significant association of airway CD8+ effector memory T cells re-expressing CD45RA (TEMRAs), but not CD8+ CD45RO+ or tissue resident memory (TRM) T cells, with asthma duration in patients with severe asthma (SA) but not mild to moderate asthma (MMA). Higher frequencies of IFN-γ+ CD8+ TEMRAs compared to IFN-γ+ CD45RO+ T cells were detected in SA airways, and the TEMRAs from SA but not MMA patients proliferated ex vivo, although both expressed cellular senescence-associated biomarkers. Prompted by the transcriptomic profile of SA CD8+ TEMRAs and proliferative response to IL-15, airway IL15 expression measured higher in SA compared to MMA patients. IL15 expression in asthmatic airways negatively correlated with lung function. Our findings add a new dimension to understanding asthma heterogeneity identifying IL-15 as a potential target for treatment.