Single-Cell Atlas of CD4+ T-Helper 2 Cells Reveals Distinct Cytokine Functions Across Diseases

Despite the prevalence of autoimmune diseases, treatment options for specific conditions remain limited. These diseases are driven by three types of inflammatory pathways, each orchestrated by different T-helper cell subsets; however, a comprehensive atlas capturing their diverse functions across conditions and tissues is lacking. One of these subsets, CD4 ⁺ T-helper type 2 (Th2) cells, is a relatively infrequent immune cell population that plays a central role in orchestrating type 2 inflammation. In this study, we developed the first comprehensive CD4 ⁺ Th2 single-cell atlas by analyzing the BioTuring database, which has data from over 300 million cells. This atlas integrates data from 52 studies, comprising a total of 39,243 cells derived from 9 major tissues, representing over 30 distinct diseases. Leveraging this atlas, we confirmed a rarely recognized CD4 ⁺ Th2 cell population co-expressing IL22 and IL13 observed exclusively in atopic dermatitis and not in other allergic conditions. By integrating single-cell data with other “omics” technologies, our analysis suggests distinct downstream effects of IL22 and IL13 , highlighting the potential for combination therapy to enhance treatment outcomes for AD patients. Additionally, by utilizing data derived from the wide range of diseases, tissues, and time points included in this atlas, we re-confirmed the unique connection between IL9 expression and conditions related to allergen exposure. Pseudotime analysis detailed CD4 ⁺ Th2 cytokine dynamics upon allergen stimulation, showing a shift from early IL2 and IL4 expression to later IL9 and IL5 , with IL13 consistently expressed, and further revealed that IL9 production was transient. Collectively, these findings reveal distinct, context-dependent CD4 ⁺ Th2 cytokine functions, opening the potential for identifying novel therapeutic strategies for allergic and inflammatory diseases.