2. Academic Validation
  3. Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22

Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22

  • Nature. 2025 Oct 1. doi: 10.1038/s41586-025-09589-5.
Fangtao Chi 1,  Qiming Zhang 1,  Jessica E S Shay 1,  Shixun Han 1,  Johanna Ten Hoeve 2,  Yin Yuan 1,  Zhenning Yang 1,  Heaji Shin 1,  Samuel Block 1,  Sumeet Solanki 3 4,  Yatrik M Shah 3 4,  Matthew G Vander Heiden 1 5 6,  Judith Agudo 7 8 9 10,  Ömer H Yilmaz 11 12 13
Affiliations

Affiliations

  • 1 Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, MIT, Cambridge, MA, USA.
  • 2 UCLA Metabolomics Center, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
  • 3 Molecular and Integrative Physiology Department, University of Michigan, Ann Arbor, MI, USA.
  • 4 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 5 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 7 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 8 Department of Immunology, Harvard Medical School, Boston, MA, USA.
  • 9 Ludwig Center at Harvard, Boston, MA, USA.
  • 10 Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA, USA.
  • 11 Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, MIT, Cambridge, MA, USA. ohyilmaz@mit.edu.
  • 12 Broad Institute of MIT and Harvard, Cambridge, MA, USA. ohyilmaz@mit.edu.
  • 13 Department of Pathology, Beth Israel Deaconess Medical Center, Massachusetts General Hospital Boston and Harvard Medical School, Boston, MA, USA. ohyilmaz@mit.edu.
PMID: 41034585 DOI: 10.1038/s41586-025-09589-5
Abstract

A fundamental question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues1-8. The mammalian small intestine is maintained by rapidly renewing LGR5+ intestinal stem cells (ISCs) that respond to macronutrient changes such as fasting regimens and obesogenic diets, yet how specific Amino acids control ISC function during homeostasis and injury remains unclear. Here we demonstrate that dietary cysteine, a semi-essential amino acid, enhances ISC-mediated intestinal regeneration following injury. Cysteine contributes to coenzyme A (CoA) biosynthesis in intestinal epithelial cells, which promotes expansion of intraepithelial CD8αβ+ T cells and their production of interleukin-22 (IL-22). This enhanced IL-22 signalling directly augments ISC reparative capacity after injury. The mechanistic involvement of the pathway in driving the effects of cysteine is demonstrated by several findings: CoA supplementation recapitulates cysteine effects, epithelial-specific loss of the cystine transporter SLC7A11 blocks the response, and mice with CD8αβ+ T cells lacking IL-22 or a depletion of CD8αβ+ T cells fail to show enhanced regeneration despite cysteine treatment. These findings highlight how coupled cysteine metabolism between ISCs and CD8+ T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.

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