The gut microbiota directs vitamin A flux to regulate intestinal T cell development

Srinivasan, T.; Dende, C.; Ruhn, K. A.; Moye, S. L.; Johnson, A.; Behrendt, C. L.; Hassell, B.; Vale, G.; Kim, J.; Lichterman, J. N.; Liang, C.; Arana, C.; Raj, P.; Zhan, X.; McDonald, J. G.; Koh, A. Y.; Hooper, L. V.

doi:10.1101/2025.09.08.674524

bioRxiv · 10.1101/2025.09.08.674524

The gut microbiota directs vitamin A flux to regulate intestinal T cell development

Srinivasan, T.·Dende, C.·Ruhn, K. A.·Moye, S. L.·Johnson, A.·Behrendt, C. L.·Hassell, B.·Vale, G.·Kim, J.·Lichterman, J. N.·Liang, C.·Arana, C.·Raj, P.·Zhan, X.·McDonald, J. G.·Koh, A. Y.·Hooper, L. V.

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Abstract

The intestinal microbiota shapes adaptive immunity, but the mechanisms remain incompletely defined. Here, we show that the microbiota initiates the movement of retinoids--dietary vitamin A derivatives including retinol and retinoic acid--through a sequential pathway from epithelial cells to myeloid cells and ultimately to T cells in the mesenteric lymph nodes (mLNs). This cellular axis is traversed over three days. Microbe-associated molecular patterns (MAMPs) initiate retinoid flux by inducing expression of serum amyloid A (SAA) proteins. These epithelial retinol-binding proteins are necessary and sufficient for epithelial-to-myeloid cell retinoid transfer and for myeloid cell migration to the mLNs. In the mLNs, microbial antigen drives retinoid transfer from myeloid cells to developing T cells, culminating in T cell retinoid uptake and transcriptional programming. This pathway is activated during postnatal development, when gut adaptive immunity is first established. These findings reveal that the microbiota programs intestinal adaptive immunity by regulating immune cell access to a nutrient-derived developmental signal. HighlightsO_LIThe gut microbiota enables vitamin A flux to developing intestinal CD4 T cells. C_LIO_LIMicrobiota-induced SAA initiates vitamin A flux along a gut myeloid-T cell axis. C_LIO_LIMicrobial molecular patterns and antigen drive distinct steps of vitamin A flux. C_LIO_LIMicrobiota-driven vitamin A flux programs intestinal T cell homing and maturation. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/674524v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@13b3906org.highwire.dtl.DTLVardef@11ceee3org.highwire.dtl.DTLVardef@87913forg.highwire.dtl.DTLVardef@50c9a0_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Srinivasan, T., Dende, C., Ruhn, K. A., Moye, S. L., Johnson, A., Behrendt, C. L., Hassell, B., Vale, G., Kim, J., Lichterman, J. N., Liang, C., Arana, C., Raj, P., Zhan, X., McDonald, J. G., Koh, A. Y., Hooper, L. V.. 2025-09-10. The gut microbiota directs vitamin A flux to regulate intestinal T cell development. https://doi.org/10.1101/2025.09.08.674524

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