Early-life Wnt4 expressing colon stromal cells orchestrate lifelong mucosal homeostasis via BMP-driven iNKT cell imprinting

  • Nat Commun. 2026 May 6. doi: 10.1038/s41467-026-72734-9.
Xi Lin  1 ,  Chloe Hyun-Jung Lee  2  3 ,  Ting Zhang  4 ,  Agne Antanaviciute  2  3 ,  Thomas Hanley  1 ,  Jonathan N Glickman  5 ,  Nikhila S Bharadwaj  6 ,  Vicki Rosen  7 ,  Jenny E Gumperz  6 ,  Matthew K Waldor  8  9  10 ,  Alison Simmons  2 ,  Thomas Gensollen  11 ,  Richard S Blumberg  12
Affiliations
  • 1. Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 2. Medical Research Council Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
  • 3. MRC Center for Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • 4. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
  • 5. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 6. Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • 7. Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
  • 8. Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA.
  • 9. Department of Microbiology, Harvard Medical School, Boston, MA, USA.
  • 10. Howard Hughes Medical Institute, Boston, MA, USA.
  • 11. Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3), Toulouse, France.
  • 12. Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 42091861 DOI: 10.1038/s41467-026-72734-9
Abstract

The early-life intestinal microenvironment plays a pivotal role in shaping immune cell development. Here, we identify a colonic Wnt4-expressing stromal cell, enriched during early-life, that promotes iNKT cell proliferation via BMP-MAPK signaling. These stromal cells are spatially associated with iNKT cells and macrophages and exhibit high Bmp2 expression during the neonatal period. Depletion of BMP2 in Wnt4+ stromal cells during, but not after, this time window leads to long-lasting reductions in iNKT cells. These stromal cells are shaped by microbial signals, as germ-free and early-life antibiotic-treated mice exhibit increased Wnt4+ stromal cell abundance and elevated Bmp2 expression, with excessive iNKT cell accumulation that lasts into adulthood. These persistent changes in iNKT cells due to early-life perturbations are associated with altered susceptibility to later-life mucosal disorders. Importantly, similar stromal cells are present in fetal and neonatal human colon, and human rBMP2 promotes iNKT cell growth. Together, our findings reveal a neonatal colonic stromal niche, orchestrated by microbial cues, that regulates colonic immune homeostasis in later-life.

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