The Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
Immunity. 2013 Feb 21;38(2):237-49. doi: 10.1016/j.immuni.2012.09.012. Epub 2013 Jan 11.
Interactions with antigen-presenting cells (APCs) interrupt T cell migration through tissues and trigger signaling pathways that converge on the activation of transcriptional regulators, including nuclear factor of activated T cells (NFAT), which control T cell function and differentiation. Both stable and unstable modes of cognate T cell-APC interactions have been observed in vivo, but the functional significance of unstable, serial contacts has remained unclear. Here we used multiphoton intravital microscopy in lymph nodes and tumors to show that while NFAT nuclear import was fast (t(1/2 max)∼1 min), nuclear export was slow (t(1/2)∼20 min) in T cells. During delayed export, nuclear NFAT constituted a short-term imprint of transient TCR signals and remained transcriptionally active for the T cell tolerance gene Egr2, but not for the effector gene Ifng, which required continuous TCR triggering for expression. This provides a potential mechanistic basis for the observation that a predominance of unstable APC interactions correlates with the induction of T cell tolerance.
与抗原呈递细胞 (APC) 的相互作用会中断 T 细胞在组织中的迁移，并触发信号通路，这些信号通路汇聚到转录调节剂的激活，包括激活的 T 细胞核因子 (NFAT)，它控制 T 细胞的功能和分化。在体内已经观察到稳定和不稳定的同源 T 细胞-APC 相互作用模式，但不稳定、连续接触的功能意义仍然不清楚。在这里，我们使用淋巴结和肿瘤中的多光子活体显微镜显示，虽然 NFAT 核内输入很快（t(1/2 max)∼1 min），但核内输出很慢（t(1/2)∼20 min）在 T 细胞中。在延迟的输出过程中，核内 NFAT 构成了短暂 TCR 信号的短期印记，并保持转录活性，用于 T 细胞耐受基因 Egr2，但不是用于效应基因 Ifng，后者需要持续的 TCR 触发才能表达。这为观察到不稳定 APC 相互作用的优势与 T 细胞耐受的诱导相关提供了潜在的机制基础。
