2025/03/25 by Sara Alonso, Harsimran Kaur, Luo Jia +9 · 1 voice
Immunology and Microbiology · #IL-33, ST2, and ILC Pathways #Immune Cell Function and Interaction #T-cell and B-cell Immunology
paper · pdf · doi:10.1101/2025.03.22.644616
openalex publication_date 2025/03/25 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/22
ABSTRACT Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IEL) provide continuous surveillance of the intestinal epithelium. We report that mice harboring a microbiota-specific hyperproliferative γδ IEL (γδ HYP ) phenotype also upregulate the expression of the ectonucleotidase CD39, a marker of regulatory γδ T cells. Enhanced TCR and IL-15 signaling correlates with a progression from a naïve-like CD39 neg γδ IEL to a more mature, tissue-adapted CD39 hi IEL population. We found that TCRγδ activation drives CD122-mediated CD39 upregulation on γδ HYP IELs and increased mucosal IL-15 further amplifies CD39 expression in these cells. Further investigation revealed that CD39 induction requires sustained exposure to the γδ HYP -associated microbiota. Moreover, CD39 hi γδ IELs exhibit a reduced capacity to produce pro-inflammatory cytokine, which may explain the lack of histopathology in γδ HYP mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on γδ HYP IELs, leading to the expansion of γδ IELs with regulatory potential.