Unravelling survival and reactivation of pathogenic CD4 type-2 tissue-resident memory T cells in allergic asthma

Asthma, affecting over 300 million people worldwide with causing half a million deaths per year, is a chronic inflammatory airway disease characterized by wheezing, cough and chest tightness due to airway obstruction. Although asthma presents as a highly heterogeneous disease with various endotypes, allergic airway inflammation predominantly propels its pathogenesis in the majority of the children and half of adults. Allergen-specific CD4 type-2 helper T (Th2) cells orchestrate local airway inflammation by producing type 2 cytokines, including IL-4, IL-5, and IL-13 which drive eosinophilic inflammation, mucus metaplasia, and airway hyperresponsiveness, and have become targets for biological treatments. However, the chronicity and persistence of asthma, even after allergen avoidance, suggests the involvement of long-lived memory CD4 T cells. Recently a population of CD4 resident memory T (TRM) cells has been identified in human asthmatic lungs. In male patients with asthma, the presence of CD4 TRM cells in the lungs has even been correlated with asthma severity. This makes them an attractive target for therapeutic strategies. However, their contribution to the persistent local airway inflammation featuring asthma remains elusive. Their low numbers and tight integration within the lung tissue architecture has posed many challenges to study this CD4 TRM population <italic>in vivo</italic>. By transferring novel in-house developed house dust mite (HDM)-specific T cell receptor transgenic CD4 T cells to a HDM-induced allergic asthma mouse model, we are able to trace a pathogenic Th2RM population over time and unravel their mechanisms of survival and reactivation within the asthmatic lung.