A Role of the IL‐13 Signal and Type 2 Conventional Dendritic Cell in the Atopic March

ABSTRACT Allergic diseases such as atopic dermatitis (AD), asthma, and food allergy originate at epithelial barrier surfaces, where environmental insults trigger immune responses. This review emphasizes the crucial role of epithelium‐derived alarmins, especially IL‐33 and TSLP, as innate danger signals (DAMPs) that establish a local type 2 milieu driving type 2 helper T (Th2) immunity. When the barrier is disrupted, local antigen presentation typically drives specific immunity; however, with severe barrier disruption, the local type 2 milieu influences immunity not only locally but also systemically, enabling distant secondary lymphoid organs (SLOs) to develop dendritic cell (DC)‐mediated Type 2 immunity and high‐affinity IgE production. Recent advances in single‐cell transcriptomics have shown that conventional dendritic cell type 2 (cDC2s) are not a single homogeneous group but consist of distinct lineages, T‐bet + cDC2A and T‐bet − cDC2B, with different developmental origins and immune functions. Notably, CD301b + cDC2 (similar to cDC2B) expresses IL‐13 receptor alpha 1 (IL‐13Rα1). Importantly, IL‐13 signaling enhances the antigen‐presenting capacity of CD301b + cDC2, thereby supporting both Th2 and T follicular helper (TFH) responses, leading to high‐affinity IgE production and systemic anaphylaxis. These observations provide a mechanistic understanding of how local skin inflammation can trigger systemic allergic reactions and open new possibilities for targeted immunotherapy focused on the IL‐13–DC axis.