上皮内淋巴细胞 (IEL)，包括 αβ 和 γδ T 细胞 (T-IEL)，不断调查并在维持胃肠道上皮细胞方面发挥着关键作用。我们发现小肠中的 T-IEL 高度表达对防御癌症很重要的细胞毒性分子。相反，结肠 T-IEL 的丰度取决于微生物组，并表现出较高的 TCF-1/TCF7 表达以及较低的效应子和细胞毒性特征，包括颗粒酶的低表达。 γδ T-IEL 中 TCF-1 的靶向缺失诱导了独特的效应谱并减少了小鼠结肠肿瘤的形成。此外，与正常健康结肠相比，人类结直肠癌（CRC）中存在的 γδ T-IEL 中的 TCF-1 表达显着降低，这与增强的 γδ T-IEL 效应表型和改善的患者生存率密切相关。我们的工作将 TCF-1 确定为结肠特异性 T-IEL 转录调节因子，可以为治疗 CRC 的新免疫治疗策略提供信息。

Intraepithelial lymphocytes (IELs), including αβ and γδ T cells (T-IELs), constantly survey and play a critical role in maintaining the gastrointestinal epithelium. We show that cytotoxic molecules important for defense against cancer were highly expressed by T-IELs in the small intestine. In contrast, abundance of colonic T-IELs was dependent on the microbiome and displayed higher expression of TCF-1/TCF7 and a reduced effector and cytotoxic profile, including low expression of granzymes. Targeted deletion of TCF-1 in γδ T-IELs induced a distinct effector profile and reduced colon tumor formation in mice. In addition, TCF-1 expression was significantly reduced in γδ T-IELs present in human colorectal cancers (CRCs) compared with normal healthy colon, which strongly correlated with an enhanced γδ T-IEL effector phenotype and improved patient survival. Our work identifies TCF-1 as a colon-specific T-IEL transcriptional regulator that could inform new immunotherapy strategies to treat CRC.