Alonso Sara, Kaur Harsimran, Jia Luo, Nguyen Mai-Uyen, Laguerta Alyssa, Fong Andrew, Skariah Neema, Argüello Rafael J, Verzi Michael P, Swamy Mahima, Lau Ken S, Edelblum Karen L
Center for Immunity and Inflammation, Department of Pathology, Immunology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA; Department of Pathology, Molecular and Cell-Based Medicine and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Program in Chemical and Physical Biology, Department of Cell and Developmental Biology, Center for Computational Systems Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Mucosal Immunol. 2025 Jul 17. doi: 10.1016/j.mucimm.2025.07.005.
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) 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 γδ IEL to a more mature, tissue-adapted CD39 IEL population. We found that TCRγδ activation drives CD122-mediated CD39 upregulation on γδ 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-associated microbiota. Moreover, CD39 γδ IELs exhibit a reduced capacity to produce pro-inflammatory cytokine, which may explain the lack of histopathology in γδ mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on γδ IELs, leading to the expansion of γδ IELs with regulatory potential.
表达γδ T细胞受体的上皮内淋巴细胞（γδ IEL）对肠道上皮进行持续监测。我们报告称，具有微生物群特异性增殖性γδ IEL（γδ）表型的小鼠也会上调外切核苷酸酶CD39的表达，CD39是调节性γδ T细胞的标志物。增强的TCR和IL-15信号传导与从幼稚样CD39 γδ IEL向更成熟、组织适应性更强的CD39 IEL群体的进展相关。我们发现，TCRγδ激活驱动γδ IEL上CD122介导的CD39上调，而增加的黏膜IL-15进一步放大了这些细胞中CD39的表达。进一步研究表明，CD39的诱导需要持续暴露于与γδ相关的微生物群。此外，CD39 γδ IEL产生促炎细胞因子的能力降低，这可能解释了γδ小鼠缺乏组织病理学变化的原因。总体而言，我们的研究确定了一种以前未被认识的机制，即改变的微生物群放大了γδ IEL上CD39的表达，导致具有调节潜力的γδ IEL扩增。
