TCF1-LEF1 Co-expression Identifies a Multipotent Progenitor Cell (T2-MPP) Across Human Allergic Diseases

Repetitive exposure to antigen in chronic infection and cancer drives T cell exhaustion, limiting adaptive immunity. In contrast, aberrant, sustained T cell responses can persist over decades in human allergic disease. To understand these divergent outcomes, we employed bioinformatic, immunophenotyping and functional approaches with human diseased tissues, identifying an abundant population of type 2 helper T (T2) cells with co-expression of TCF7 and LEF1, and features of chronic activation. These cells, which we termed T2-multipotent progenitors (T2-MPP) could self-renew and differentiate into cytokine-producing effector cells, regulatory T (T) cells and follicular helper T (T) cells. Single-cell T-cell-receptor lineage tracing confirmed lineage relationships between T2-MPP, T2 effectors, T cells and T cells. T2-MPP persisted despite in vivo IL-4 receptor blockade, while thymic stromal lymphopoietin (TSLP) drove selective expansion of progenitor cells and rendered them insensitive to glucocorticoid-induced apoptosis in vitro. Together, our data identify T2-MPP as an aberrant T cell population with the potential to sustain type 2 inflammation and support the paradigm that chronic T cell responses can be coordinated over time by progenitor cells.