학술논문
TCF1–LEF1 co-expression identifies a multipotent progenitor cell (TH2-MPP) across human allergic diseases
Document Type
Article
Author
Kratchmarov, Radomir; Djeddi, Sarah; Dunlap, Garrett; He, Wenqin; Jia, Xiaojiong; Burk, Caitlin M.; Ryan, Tessa; McGill, Alanna; Allegretti, Jessica R.; Kataru, Raghu P.; Mehrara, Babak J.; Taylor, Erin M.; Agarwal, Shailesh; Bhattacharyya, Neil; Bergmark, Regan W.; Maxfield, Alice Z.; Lee, Stella; Roditi, Rachel; Dwyer, Daniel F.; Boyce, Joshua A.; Buchheit, Kathleen M.; Laidlaw, Tanya M.; Shreffler, Wayne G.; Rao, Deepak A.; Gutierrez-Arcelus, Maria; Brennan, Patrick J.
Source
Nature Immunology; 20240101, Issue: Preprints p1-14, 14p
Subject
Language
ISSN
15292908; 15292916
Abstract
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 (TH2) cells with co-expression of TCF7and LEF1, and features of chronic activation. These cells, which we termed TH2-multipotent progenitors (TH2-MPP) could self-renew and differentiate into cytokine-producing effector cells, regulatory T (Treg) cells and follicular helper T (TFH) cells. Single-cell T-cell-receptor lineage tracing confirmed lineage relationships between TH2-MPP, TH2 effectors, Tregcells and TFHcells. TH2-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 TH2-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.