The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
School of Pharmaceutical Sciences, Shandong First Medical University, Taian, China.
Immunology. 2022 Oct;167(2):233-246. doi: 10.1111/imm.13533. Epub 2022 Jul 12.
Intestinal intraepithelial lymphocytes (IELs) play a crucial role in host defence against pathogens in the intestinal mucosa. The development of intestinal IELs is distinct from peripheral T lymphocytes and remains elusive. Fas-associated protein with death domain (FADD) is important for T cell development in the thymus. Here we describe a novel function of FADD in the IEL development. FADD (S191A), a mouse FADD mutant at Ser191 to Ala mimicking constitutively unphosphorylated FADD, promoted a rapid expansion of TCRαβ IELs, not TCRγδ IELs. Mechanism investigation indicated that the dephosphorylation of FADD was required for cell activation mainly in TCRαβ CD8 T cells. Consistently, FADD (S191A) as dephosphorylated FADD led to a high NF-κB activation in the TCR-dependent cell expansion. In addition, The FADD (S191A)-induced abnormal IEL populations resulted in the increased incidence and severity of colitis in mice. In summary, FADD signalling is involved in the intestinal IEL development and might be a regulator for intestinal mucosal homeostasis.
肠上皮内淋巴细胞 (IELs) 在宿主防御肠道黏膜病原体中发挥着至关重要的作用。肠上皮内淋巴细胞的发育与外周 T 淋巴细胞不同，目前仍不清楚其具体机制。 Fas 相关死亡结构域蛋白 (FADD) 对于胸腺中 T 细胞的发育非常重要。在这里，我们描述了 FADD 在 IEL 发育中的一个新功能。FADD（S191A），一种模拟持续非磷酸化 FADD 的丝氨酸 191 突变为丙氨酸的小鼠 FADD 突变体，促进了 TCRαβ IELs 的快速扩增，而不是 TCRγδ IELs。机制研究表明，FADD 的去磷酸化对于 TCRαβ CD8 T 细胞的细胞激活是必需的。一致地，FADD（S191A）作为去磷酸化的 FADD 导致 NF-κB 在 TCR 依赖性细胞扩增中的高激活。此外，FADD（S191A）诱导的异常 IEL 群体导致小鼠结肠炎的发生率和严重程度增加。总之，FADD 信号通路参与了肠道 IEL 的发育，可能是肠道黏膜稳态的调节剂。
