CD8⁺ TEMRAs in severe asthma associate with asthma symptom duration and escape proliferation arrest

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Abstract

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 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 with IFN-γ+CD45RO+ T cells were detected in SA airways, and the TEMRAs from patients with SA but not MMA 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 was higher in patients with SA compared with MMA. Additionally, IL15 expression in asthmatic airways negatively correlated with lung function. Our findings add what we believe is a new dimension to understanding asthma heterogeneity, identifying IL-15 as a potential target for treatment.

Authors

Richard P. Ramonell, Timothy B. Oriss, Jessica C. McCreary-Partyka, Sagar L. Kale, Nicole R. Brandon, Mark A. Ross, Marc C. Gauthier, Molin Yue, Taylor J. Nee, Sudipta Das, Wei Chen, Alok V. Joglekar, Prabir Ray, Claudette M. St Croix, Dhivyaa Rajasundaram, Sally E. Wenzel, Anuradha Ray