A unique intestinal epithelial cell that expresses canonical lymphoid genes

Bhattacharya, S.; Badarinath, K.; Tie, G.; Singh, P. N. P.; Eskiocak, O.; He, R.; Bao, B.; Lee, S.-H.; Snapper, S. B.; Huang, K.; Goldenring, J. R.; Beyaz, S.; Shivdasani, R. A.

doi:10.64898/2026.10.21.760658

bioRxiv · 10.64898/2026.10.21.760658

A unique intestinal epithelial cell that expresses canonical lymphoid genes

Bhattacharya, S.·Badarinath, K.·Tie, G.·Singh, P. N. P.·Eskiocak, O.·He, R.·Bao, B.·Lee, S.-H.·Snapper, S. B.·Huang, K.·Goldenring, J. R.·Beyaz, S.·Shivdasani, R. A.

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Abstract

Enterocytes and intestinal secretory cells harbor innate immunity. However, certain transcriptional programs -even beyond rearranged T- and B-cell receptor genes- are considered the exclusive purview of adaptive immune cells, including abundant and diverse intestinal intra-epithelial lymphocytes (IELs). Here, we identify and characterize columnar intestinal secretory cells that co-express classic epithelial and lymphoid genes, including Ptprc, Cd3e, Cd8a, and Gzma/b but not T- or B-cell receptors. These previously unrecognized epithelium-derived lymphoid-like cells (EDLCs) differ from any known resident cell type, including IELs or tuft cells. Rare in healthy mouse and human intestines, their numbers increase upon IL-25 stimulation or IL-10 receptor deficiency in vivo and upon IL-13 stimulation in vitro. EDLC chromatin is uniquely accessible at thousands of cis-elements, including lymphoid and epithelial loci. These findings reveal a transcriptionally and epigenetically distinct intestinal epithelial derivative that expresses prominent lymphoid character.

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Bhattacharya, S., Badarinath, K., Tie, G., Singh, P. N. P., Eskiocak, O., He, R., Bao, B., Lee, S.-H., Snapper, S. B., Huang, K., Goldenring, J. R., Beyaz, S., Shivdasani, R. A.. 2026-10-26. A unique intestinal epithelial cell that expresses canonical lymphoid genes. https://doi.org/10.64898/2026.10.21.760658

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