A unique subset of allergen specific T helper 2+17 tissue resident memory cells is established in a mouse model of allergic inflammation

Introduction/Rationale: Asthma is one of the most common chronic respiratory diseases. Anamnestic inflammation in asthma is sustained by allergen-specific tissue-resident memory (TRM) CD4⁺ T cells. In addition to the Th2 pathway, components of the Th17 response have been identified as contributors to moderate and severe asthma. Of note, IL-17 – driven airway inflammation is resistant to steroids and to current treatment. A subset of antigen-specific CD4⁺ memory T cells co-expressing T helper 2 and T helper 17 markers (Th2+17 cells) is enriched in individuals with refractory asthma.

Methods: To investigate TRM2 cell heterogenicity in asthma, a well-established house dust mite (HDM) allergen model in mice was employed and Il13-Cre-mediated lineage-tracing of TRM2 cells was performed.

Results: Single cell RNA sequencing (scRNAseq) of lineage-labelled Th2-TRMs identified a major TRM2 subpopulation (Gata3+ only) and additional subpopulations that co-expressed specific markers of Th1 (TRM2+1), Th17 (TRM2+17), and Treg (TRM2+reg) lineages, which reveals significant heterogeneity of allergen-specific, Th2-TRMs in the lung. In addition, recent findings revealed that antigen-specific TRM2+17 cells persist in the mouse lungs for up to one year after HDM challenge and are reactivated upon subsequent allergen re-exposure.

Conclusion: Th2+17 TRMs represent a previously uncharacterized population with potential pathogenic relevance in chronic asthma. Follow-up experiments are investigating how genetic background and environmental stimuli influence the regulation and persistence of Th2+17 TRMs. By focusing on a novel TRM2+17 cell subset implicated in treatment-resistant asthma, our ultimate goal is to elucidate the mechanisms regulating this population to enable the development of effective therapeutics.