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Publications

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Ppublish 42 citations

PubMed: 38589618 DOI: 10.1038/s41590-024-01803-2

TCF1-LEF1 co-expression identifies a multipotent progenitor cell (T2-MPP) across human allergic diseases.

Nat Immunol 25(5):902-915

Authors: Radomir Kratchmarov, Sarah Djeddi, Garrett Dunlap, Wenqin He, Xiaojiong Jia, Caitlin M Burk, Tessa Ryan, Alanna McGill, Jessica R Allegretti, Raghu P Kataru, Babak J Mehrara, Erin M Taylor, Shailesh Agarwal, Neil Bhattacharyya, Regan W Bergmark, Alice Z Maxfield, Stella Lee, Rachel Roditi, Daniel F Dwyer, Joshua A Boyce, Kathleen M Buchheit, Tanya M Laidlaw, Wayne G Shreffler, Deepak A Rao, Maria Gutierrez-Arcelus, Patrick J Brennan

Affiliations

  • Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Division of Rheumatology, Inflammation, Immunity, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Center for Immunology and Inflammatory Diseases and Food Allergy Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Division of Plastic and Reconstructive Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard University, Boston, MA, USA.
  • Massachusetts Eye & Ear Institute, Harvard Medical School, Boston, MA, USA.
  • Division of Otolaryngology Head and Neck Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Center for Surgery and Public Health, Brigham and Women's Hospital, Boston, MA, USA.
  • Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

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 (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.

MeSH

Cells, Stem Cells, Immunity, T-Lymphocytes

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