Control of the Functional Fate of CD4 T Cells by LncRNA-Switch

摘要 肠道粘膜上皮分离抗原的最佳免疫调节是必不可少的。 来自体内无菌核心的丰富的肠腔。除了形成物理屏障外，上皮细胞 也执行重要的消化功能和任何组织损伤，由入侵的病原体或过量 炎症可能会危及这一关键边界的完整性。因此，粘膜免疫系统是 面对独特的挑战，既要提供最佳和直接的保护，又要以最少的时间这样做 组织受损。这种进退两难的局面给免疫细胞施加了持续不断的压力，要求其调整自身的免疫能力。 以一种与防御角色相适应的方式发挥作用，能够保护粘膜边界，但不能破坏它。 这对CD4T辅助细胞(Th)来说尤其是一个问题，它有可能分化为Treg和 抑制保护性免疫反应或对炎性效应细胞，如Th17细胞 过度的炎症和引起严重的免疫病理。最近，我们发现成熟的CD4T细胞 迁移到肠上皮的细胞通过从功能上转移到肠道上皮来适应环境 抑制或炎症Th的命运，而不是重新编程成为保护性的CD8样细胞毒效应因子 细胞。将CD4细胞重新编程为细胞毒性T淋巴细胞(CTL)是使其适应的关键过程 在重新编程过程中对粘膜环境和缺陷导致高度的生成 炎症性Th17T细胞，可导致肠道组织严重破坏。虽然非常重要， 对于驱动成熟过程中重编程过程的分子机制或因素，我们一无所知 CD4T细胞。然而，初步研究导致发现了一种新的长非编码RNA(LncRNA)， 我们称之为Switch，因为我们发现它在CD4CTL前体细胞中唯一表达，但 更重要的是因为它的表达直接与依赖Runx3的CTL的启动有关 基因转录程序和RoRγt-和Foxp3控制的CD4Th体外命运的关闭- 以及体内激活的成熟CD4T细胞。此外，我们还发现，开关功能的丧失会损害 CD4Th细胞重新编程为CTL并导致高致病性Th17T细胞在 肠子。这些观察结果支持Switch作为CD_4可塑性的“主调节器”的作用以及 以一种方式适应粘膜CD4T细胞功能命运的机制的关键控制者 与肠道粘膜界面的独特挑战相兼容。我们建议在此澄清 这种新的lncRNA开关能够作为CD4T的中枢发挥作用的分子机制 细胞的可塑性超出了Th的命运，并将成熟的CD4T细胞重定向到Runx3控制的CTL 抑制导致CD4T细胞功能分化为 炎症性RORγt控制Th1 7细胞或抑制Foxp3控制的Treg。

SUMMARY Optimal immune regulation is essential at the mucosal epithelium of the intestine that separates the antigen- rich gut lumen from the sterile inner core of the body. In addition to forming a physical barrier, the epithelium also carries out vital digestive functions and any tissue damage, induced by invading pathogens or excessive inflammation can jeopardize the integrity of this critical border. Consequently, the mucosal immune system is faced with the unique challenge to provide optimal and immediate protection but also to do so with the least damage to the tissue. This dilemma imposes a constant pressure for the immune cells to adjust their immune function in a way that is compatible with a defensive role able to protect the mucosal border but not destroy it. This is especially an issue for CD4 T helper (Th) cells, which have the potential to differentiate to Treg and suppress protective immune responses or to inflammatory effector cells like the Th17 cells that can initiate excessive inflammation and induce severe immune pathology. Recently, we discovered that mature CD4 T cells that migrate to the intestinal epithelium adapt to the environment by functionally divert from their suppressive or inflammatory Th fate but instead reprogram to become protective CD8-like cytotoxic effector cells. The reprogramming of CD4 cells to cytotoxic T lymphocytes (CTL) is a critical process that adapts them to the mucosal environment and defects in the reprogramming process lead to the generation of highly inflammatory Th17 T cells that cause severe tissue destruction in the intestine. Although extremely important, nothing is known about the molecular mechanism or factors that drive the reprogramming process in mature CD4 T cells. Preliminary studies however lead to the discovery of a novel long non-coding RNA(LncRNA), which we have called, Switch, because we found that it is uniquely expressed in CD4 CTL precursor cells but more importantly because its expression directly associates with the switching-on of the Runx3-dependent CTL gene transcription program and the switching-off of the RORγt- and Foxp3-controlled CD4 Th fates in in vitro- and in vivo-activated mature CD4 T cells. In addition, we found that loss-of-function of Switch impaired the reprogramming of CD4 Th cells to CTL and led to the accumulation of highly pathogenic Th17 T cells in the intestine. These observations support a role for Switch as a “master regulator” of CD4 plasticity as well as a critical controller of the mechanism to adapt the functional fate of mucosal CD4 T cells in a way that is compatible with the unique challenges at the mucosal interface of the intestine. We propose here to elucidate the molecular mechanisms by which this novel LncRNA, Switch, is able to function as a central hub for CD4 T cell plasticity that stretches beyond the Th fates and re-directs mature CD4 T cells to the Runx3-controlled CTL lineage fate while suppressing the alternative pathways that lead to functional differentiation of CD4 T cells into inflammatory RORγt controlled Th17 cells or suppressive Foxp3-controlled Treg.