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

Area of Science:

• Gastroenterology
• Immunology
• Cell Biology

Background:

• Mucosal healing relies on epithelial and immune cell communication, processes disrupted in inflammatory bowel disease (IBD).
• Tumor necrosis factor superfamily member 13 (TNFSF13) is crucial for B cell function, but its role in colonic epithelial cells and IBD is unclear.

Purpose of the Study:

• To investigate the functional impact of a novel monoallelic TNFSF13 variant on colonic epithelial cells and their interaction with B cells.
• To elucidate the role of epithelial TNFSF13 in regulating colonic epithelial homeostasis and its potential contribution to IBD pathogenesis.

Main Methods:

• Utilized patient biopsies, tissue-derived colonoids, and induced pluripotent stem cell (iPSC)-derived colon organoids to model TNFSF13 variant effects.
• Employed single-cell RNA-sequencing, flow cytometry, co-immunoprecipitation, and imaging mass cytometry to analyze cellular responses and interactions.
• Performed co-culture experiments with memory B cells to assess the impact on immunoglobulin A (IgA)+ plasma cell production.

Main Results:

• TNFSF13 variant colonoids showed over 50% reduced TNFSF13 secretion, increased epithelial proliferation, and decreased apoptosis.
• FAS was identified as the primary colonic epithelial receptor for TNFSF13.
• Increased epithelial-associated B cells were observed in TNFSF13 variant colon tissue.
• Co-culture with memory B cells revealed reduced IgA+ plasma cell generation in TNFSF13 variant colonoid settings.

Conclusions:

• Epithelial TNFSF13 acts as a key regulator of colonic epithelial cell growth and proliferation.
• TNFSF13 influences epithelial crosstalk with B cells, impacting IgA+ plasma cell differentiation.
• These findings suggest a novel mechanism by which epithelial TNFSF13 dysfunction may contribute to inflammatory bowel disease.