Microbiota promote enhanced CD39 expression in gd intraepithelial lymphocytes through the activation of TCR and IL-15 signaling.

Intraepithelial lymphocytes expressing the gd T cell receptor (gd IEL) provide continuous surveillance of the intestinal epithelium. We report that mice harboring a microbiota-specific hyperproliferative gd IEL (gdHYP) phenotype also upregulate the expression of the ectonucleotidase CD39, a marker of regulatory gd T cells. Enhanced TCR and IL-15 signaling correlates with a progression from a naïve-like CD39neg gd IEL to a more mature, tissue-adapted CD39hi IEL population. We find that TCRgd activation drives CD122-mediated CD39 upregulation on gdHYP IELs and increased mucosal IL-15 further amplifies CD39 expression in gdHYP IELs. Notably, CD39 induction requires sustained exposure to the gdHYP-associated microbiota. Increased IL-15 signaling prolongs IEL survival and enhances gdHYP IEL bioenergetic potential. Notably, CD39hi gd IELs produce less pro-inflammatory cytokine, which may explain the lack of histopathology in gdHYP mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on gdHYP IELs, leading to the expansion of gd IELs with regulatory potential.