Revisiting CD8+ T Cells in Allergy: The Emerging Role of Tc2 Cells.

Type 2 CD8+ T (Tc2) cells are increasingly recognised as contributors to allergic inflammation, yet remain less well understood than T helper 2 (Th2) cells and Group 2 innate lymphoid cells (ILC2s). Defined by production of IL-4, IL-5 and IL-13, Tc2 cells have been implicated in eosinophilic inflammation, airway hyperresponsiveness, mucus production, and chronic tissue inflammation in diseases including asthma, atopic dermatitis, and chronic rhinosinusitis. Emerging evidence suggests that Tc2 differentiation and function are shaped by alarmins, lipid mediators, hypoxia, and immunometabolic pathways involving glycolysis, fatty acid metabolism, and serotonin signalling. Compared with Th2 cells, Tc2 cells may exhibit distinct features including tissue adaptation, responsiveness to innate inflammatory cues, and relative corticosteroid resistance, suggesting non-redundant roles in sustaining chronic allergic inflammation. Current biologic therapies targeting Type 2 pathways likely influence Tc2 activity, although their effects on Tc2-driven inflammation remain unclear. Here, we review current understanding of Tc2 cell phenotype, differentiation, immunometabolic regulation, and effector functions, and summarise evidence linking Tc2 cells to allergic disease. We also highlight key unanswered questions regarding Tc2 lineage stability, tissue residency, antigen specificity, and therapeutic targeting. Together, these findings position Tc2 cells as emerging amplifiers of Type 2 immunity and potential contributors to treatment-resistant allergic disease.