Pathogenic type-2 immunity beyond allergy: the role of Th2 cell heterogeneity in helminth infections.

Type 2 immunity is a defining feature of helminth infection and is traditionally viewed as protective, promoting parasite expulsion, tissue repair, and/or suppression of bystander antigens. However, work in allergic disease has demonstrated that Th2 cells are not functionally uniform but instead comprise specialized subsets, including highly differentiated pathogenic Th2 populations characterized by sustained IL-5/13 production, epithelial alarmin responsiveness, and stable tissue residency. The presence of these cells is associated with immunopathology and worse clinical outcomes. Interestingly, many helminth-associated pathologies, including granulomatous fibrosis in schistosomiasis, pulmonary injury during Ascaris larval migration, and eosinophil-driven inflammation in filariasis, mirror mechanisms attributed to pathogenic Th2 cells in allergy. Yet Th2 responses in helminth infections remain largely defined by bulk cytokine production rather than discrete cellular programs. Here, we synthesize emerging evidence from human infection studies and experimental models demonstrating the expansion of highly differentiated Th2 subsets during helminth infection that phenotypically and transcriptionally resemble pathogenic Th2 cells defined in allergy. We examine how these subsets associate with tissue pathology, symptom severity, or altered immune responsiveness, while also highlighting important context-dependent differences in regulatory and effector balance. This review challenges the traditional view of helminth-induced Th2 immunity as a uniform response and instead supports a model in which specialized Th2 programs differentially contribute to protection, pathology, and immune modulation during infection. We propose that resolving this heterogeneity through high-dimensional and spatial approaches will be essential to redefine helminth-induced type 2 immunity and to distinguish protective from pathology-driving programs within host-parasite interactions.