Background: Allergic asthma (AA) in childhood is characterized by a dominance of type 2 immunity and inefficient counter-regulation by type 1 immunity and/or Tregs among other mechanisms. However, a detailed analysis of T cells associated with paediatric AA is still needed. Methods: High-dimensional mass cytometry, algorithmic analysis and manual gating were applied to define the peripheral T-cell signature in treatment-naïve childhood AA. Results: The analysis revealed a changed T-cell profile in children with AA in comparison to healthy controls (HC) consisting of: (i) a lower frequency of memory CD8+ T cells, (ii) an overrepresentation of TIGIT+ICOS+ Th2 cells connected to a more symptomatic disease with allergic comorbidity and eosinophilia, and (iii) an altered Treg compartment. Within Tregs, the naïve/resting fraction was enriched in children with AA vs HC, it associated inversely with memory CD8+ T cells, and was linked to a lung function decline. Moreover, the ratio of TIGIT+ICOS+ Th2 cells to dysbalanced effector (e)Treg clusters significantly associated with eosinophilia. Thus, dysregulated Treg fractions were linked to a lung function and, on the other hand, to eosinophilia via TIGIT+ICOS+Th2 cells. The association of altered Treg clusters with the AA phenotype in ROC analysis underscored the importance of changes in the Treg compartment. Conclusions: Our approach identifies a unique T-cell signature of childhood AA and provides insights for pathophysiological involvement of dysbalanced Tregs, TIGIT+ICOS+ Th2 cells and CD8+ T memory cells. This can be useful for immunomonitoring, immunomodulation and for further studies in childhood AA.

Mass cytometry-based identification of a unique T-cell signature in childhood allergic asthma Short title: T-cell signature in paediatric AA

A document by Jana Eckert. Click on the document to view its contents.

A document by Hartmann Raifer. Click on the document to view its contents.

Background: Allergic diseases are the most prevalent chronic childhood diseases resulting in a massive societal and economic burden for the community and a significant reduction of health-related quality of life (HRQoL) for affected families. The project CHAMP (CHildhood Allergy and tolerance: bioMarkers and Predictors) was funded in 2017 by the German Federal Ministry for Education and Research. Methods: CHAMP investigates the determinants of different allergic diseases from birth to adolescence to identify clinically relevant biomarkers predicting onset, progression, remission and severity. Data on HRQoL and patient’s needs and requirements were collected, supported by the German Asthma and Allergy Association (DAAB). Using validated questionnaires and outpatient visits, eight subprojects analysed allergic diseases in epidemiological or clinical cohorts (more than 2500 children/adolescents), sampling numerous biomaterials to assess omics on several levels. Murine models disentangled underlying mechanisms of early tolerance, translating findings from the cohorts to models and vice versa. Results: The DAAB survey, including 851 participants, showed that 83% were interested in prediction of the course of different current allergic diseases and future manifestation. 86% of participants considered doctor’s specialized training and their education as highly important, over 70% chose research for allergy understanding and prevention as critical. CHAMP addresses these needs. Common SOPs have been established and recruitment is ongoing. Conclusion: The DAAB patient survey confirmed the critical need for translational allergy research. CHAMP envisions to predict onset, tolerance and remission of allergic diseases and to identify disease sub-phenotypes for future development of preventive strategies and novel avenues for therapeutic options.