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<p>The early-life intestinal microenvironment plays a pivotal role in shaping immune cell development. Here, we identify a colonic <i>Wnt4</i>-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 <i>Bmp2</i> expression during the neonatal period. Depletion of BMP2 in <i>Wnt4</i><sup><i>+</i></sup> 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 <i>Wnt4</i><sup><i>+</i></sup> stromal cell abundance and elevated <i>Bmp2</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月6日

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  • Xi Lin,
  • Chloe Hyun-Jung Lee,
  • Ting Zhang,
  • Agne Antanaviciute,
  • Thomas Hanley,
  • Jonathan N. Glickman,
  • Nikhila S. Bharadwaj,
  • Vicki Rosen,
  • Jenny E. Gumperz,
  • Matthew K. Waldor,
  • Alison Simmons,
  • Thomas Gensollen,
  • Richard S. Blumberg

摘要

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.