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

Chi, F.; Zhang, Q.; Shay, J. E. S.; Hoeve, J. T.; Yuan, Y.; Yang, Z.; Shin, H.; Solanki, S.; Shah, Y. M.; Agudo, J.; Yilmaz, O. H.

doi:10.1101/2025.02.15.638423

bioRxiv · 10.1101/2025.02.15.638423

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

Chi, F.·Zhang, Q.·Shay, J. E. S.·Hoeve, J. T.·Yuan, Y.·Yang, Z.·Shin, H.·Solanki, S.·Shah, Y. M.·Agudo, J.·Yilmaz, O. H.

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Abstract

A critical question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues. The mammalian small intestine, a vital digestive organ that absorbs nutrients, is maintained by rapidly renewing Lgr5+ intestinal stem cells (ISCs) at the intestinal crypt base. While Lgr5+ ISCs drive intestinal adaptation by altering self-renewal and differentiation divisions in response to diverse diets such as high-fat diets and fasting regimens, little is known about how micronutrients, particularly amino acids, instruct Lgr5+ ISC fate decisions to control intestinal homeostasis and repair after injury. Here, we demonstrate that cysteine, an essential amino acid, enhances the ability of Lgr5+ ISCs to repair intestinal injury. Mechanistically, the effects of cysteine on ISC-driven repair are mediated by elevated IL-22 from intraepithelial CD8{beta}+ T cells. 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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Chi, F., Zhang, Q., Shay, J. E. S., Hoeve, J. T., Yuan, Y., Yang, Z., Shin, H., Solanki, S., Shah, Y. M., Agudo, J., Yilmaz, O. H.. 2025-02-16. Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22. https://doi.org/10.1101/2025.02.15.638423

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