Molecular requirements of pathogenic Th2 cell differentiation in allergic airway disease

Th2 cells were originally described as a homogeneous population capable of simultaneously producing interleukin (IL)-4, IL-5, and IL-13, thereby playing a central role in allergic asthma and related conditions. Subsequent studies have revealed substantial heterogeneity within the Th2 lineage, with distinct subpopulations defined by unique surface markers and cytokine profiles. Of particular interest are pathogenic Th2 subsets, referred to as peTh2, Tpath2, or Th2A, that exhibit specialised effector functions and actively drive allergic disease. These pathogenic Th2 (pTh2) cells have been identified across a wide range of human allergic conditions, including conjunctivitis, allergic rhinitis, chronic rhinosinusitis, atopic dermatitis, IgE-mediated food allergy, and eosinophilic gastrointestinal disorders such as eosinophilic esophagitis, underscoring their broad clinical relevance. The molecular requirements for early pTh2 differentiation, as well as the transcriptional networks and epigenetic mechanisms that regulate their maturation, remain incompletely understood. Moreover, pTh2 cells themselves display considerable heterogeneity, circulating in the blood, and residing in secondary lymphoid organs, and peripheral tissues. This review highlights recent advances in the heterogeneity, differentiation, and molecular regulation of pTh2 cells, with a particular focus on their roles in eosinophilic asthma. We review the signalling pathways that drive pTh2 differentiation, their transcriptional and epigenetic regulation, and the diverse subpopulations they encompass. These insights offer a foundation for developing targeted therapies to mitigate type 2-driven allergic inflammation.