TNFSF13 insufficiency disrupts human colonic epithelial cell-mediated B cell differentiation

Ma, X.; Dawany, N.; Kondo, A.; Maurer, K.; Karakasheva, T.; Shraim, R.; Williams, P. A.; Parham, L. R.; Simon, L. A.; Danan, C. H.; Conrad, M. A.; Piccoli, D. A.; Devoto, M.; Sullivan, K. E.; Kaestner, K. H.; Kelsen, J. R.; Hamilton, K. E.

doi:10.1101/2024.09.23.614260

bioRxiv · 10.1101/2024.09.23.614260

TNFSF13 insufficiency disrupts human colonic epithelial cell-mediated B cell differentiation

Ma, X.·Dawany, N.·Kondo, A.·Maurer, K.·Karakasheva, T.·Shraim, R.·Williams, P. A.·Parham, L. R.·Simon, L. A.·Danan, C. H.·Conrad, M. A.·Piccoli, D. A.·Devoto, M.·Sullivan, K. E.·Kaestner, K. H.·Kelsen, J. R.·Hamilton, K. E.

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Abstract

Cytokines mediating epithelial and immune cell interactions modulate mucosal healing-a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturation and function, but roles for epithelial TNFSF13 and putative contribution to inflammatory bowel disease are poorly understood. We evaluated functional consequences of a novel monoallelic TNFSF13 variant using biopsies, tissue-derived colonoids and induced pluripotent stem cell (iPSC)-derived colon organoids. TNFSF13 variant colonoids exhibited a >50% reduction in secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis, which was confirmed in iPSC-derived colon organoids. Single cell RNA-sequencing, flow cytometry, and co-immunoprecipitation identified FAS as the predominant colonic epithelial receptor for TNFSF13. Imaging mass cytometry revealed an increase in epithelial-associated B cells in TNFSF13 variant colon tissue sections. Finally, TNFSF13 variant colonoids co-cultured with memory B cells demonstrated a reduction in the production of IgA+ plasma cells compared to control colonoid co-cultures. Our findings support a role for epithelial TNFSF13 as a regulator of colonic epithelial growth and epithelial crosstalk with B cells. SUMMARYEpithelial TNFSF13 regulates colonic epithelial growth and epithelial-B cell interactions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/614260v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1e5b892org.highwire.dtl.DTLVardef@b8857forg.highwire.dtl.DTLVardef@448b95org.highwire.dtl.DTLVardef@2820e2_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Ma, X., Dawany, N., Kondo, A., Maurer, K., Karakasheva, T., Shraim, R., Williams, P. A., Parham, L. R., Simon, L. A., Danan, C. H., Conrad, M. A., Piccoli, D. A., Devoto, M., Sullivan, K. E., Kaestner, K. H., Kelsen, J. R., Hamilton, K. E.. 2024-09-23. TNFSF13 insufficiency disrupts human colonic epithelial cell-mediated B cell differentiation. https://doi.org/10.1101/2024.09.23.614260

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