A twist in the tail: Of T cell subsets and disease.
A twist in the tail: Of T cell subsets and disease.
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尾巴的扭曲：T 细胞亚群和疾病。
DOI：
10.1084/jem.20231423
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Pillai,Shiv
中科院分区：
文献类型：
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作者：
Pillai,Shiv
关键 T 细胞信号转导适配器胞质尾部的点突变产生了一种类似于人类纤维化炎症疾病的啮齿动物疾病模型，该模型已成为由细胞毒性 CD4+ T 细胞驱动的一系列人类疾病的原型。这些疾病不能使用广泛使用的 1 型、2 型和 3 型免疫机制范式进行分类。在过去的几十年里，出现了两种极其有效、广泛使用且通常“非特异性”的疗法，可以被视为“现代类固醇”。这些疗法，即静脉注射 IgG 和抗 CD20 介导的 B 细胞耗竭，最初是为其他治疗适应症而开发的，但如今已广泛用于不同的慢性炎症和自身免疫性疾病。虽然在某些自身抗体发挥关键作用的疾病中使用 B 细胞消除的方法相对容易理解，但除了这些疾病之外，还有多种炎症性疾病，B 细胞消除已被证明非常有效，尽管这些疾病的直接驱动因素可能是 T 细胞。在许多以组织炎症为特征的疾病中，T 细胞和 B 细胞会浸润组织。但 B 细胞如何促进此类疾病的诱发、维持或恶化呢？ T 细胞信号传导适配器的研究中出现了一些线索。 LAT（T 细胞激活连接子）是与 TCR 信号传导相关的关键适配器。它有一个非常短的、长 3 个氨基酸的胞外结构域，以及一个长 236 个氨基酸并包含 9 个酪氨酸残基的细胞质尾。二十多年前，Aguado et al.(2002) 和 Sommers et al.(2002) 分别证明纯合子 LAT Y136F 敲入小鼠的胸腺 T 细胞发育受到损害。这些小鼠还表现出外周淋巴细胞增殖并迅速形成自身免疫表型。 PLCγ1 募集和激活需要酪氨酸 136（人 LAT 中的酪氨酸 132）；下游钙信号传导在突变 T 细胞中被消除。后来的研究表明（Koonpaew et al., 2006），这些小鼠的胸腺调节性 T 细胞（Treg）发育存在缺陷，并且外周常规 T 细胞与 Treg 的比例非常高；这可能有助于解释所观察到的广泛的自身免疫表型。 Joachim 等人 (2023) 使用单细胞转录组学方法连续检查了 LAT Y136F 小鼠出生后不同时间脾脏中的免疫细胞，他们还在脾脏和肺部使用高维流式细胞术来检查浸润组织并可能是组织炎症驱动因素的 T 和 B 细胞亚群。这些小鼠中 T 细胞上的 TCR 水平较低，T 细胞的重新触发很大程度上取决于 CD28 的连接。这些小鼠的细胞变化有一个有趣的方面，类似于一系列人类炎症性疾病中观察到的变化。这些疾病中炎症和纤维化的病理变化最好归因于细胞毒性 CD4+ T 细胞 (CD4+ CTL) 和活化的 B 细胞以及可能其次是 CD8+ T 细胞的浸润。 CD4+ CTL 最初是在病毒感染和病毒控制的背景下研究的。在有关 IgG4 相关疾病（IgG4-RD；Mattoo 等人，2016）的自身免疫性疾病发病机制的研究中，这些细胞最初与组织损伤、炎症和纤维化有关。这种疾病的特征是许多不同器官中缓慢生长的炎性纤维化肿块，以及 T 和 B 细胞的组织浸润。循环 IgG4 水平升高，其他 IgG 同型也升高，许多患者的 IgE 也升高。 B 细胞治疗后几周内即可观察到显着的临床改善……
A point mutation in the cytoplasmic tail of a key T cell signaling adaptor resulted in a rodent disease model that resembles a human fibrotic inflammatory disease that has served as a prototype for a set of human diseases driven by cytotoxic CD4+ T cells. These diseases cannot be categorized using the widely used type 1, type 2, and type 3 immune mechanism paradigms. In the last few decades, two extremely effective, widely used, and generally “nonspecific” therapeutics have emerged that could be considered “modern-day steroids.” These therapies, intravenous IgG and anti-CD20–mediated B cell depletion, were originally developed for other therapeutic indications, but are widely used today in disparate chronic inflammatory and autoimmune diseases. While the use of B cell depletion in some diseases in which autoantibodies play a crucial role is relatively easy to appreciate, beyond those disorders, there is a wide range of inflammatory diseases in which B cell depletion has proven very effective, even though the immediate drivers of these diseases are likely T cells. T and B cells infiltrate tissues in many diseases characterized by tissue inflammation. But how do B cells contribute to the induction, maintenance, or exacerbation of such diseases? Some clues have emerged from the study of a T cell signaling adaptor. LAT (linker for activation of T cells) is a key adaptor of relevance to TCR signaling. It has a very short, three-amino-acid-long extracellular domain, and a cytoplasmic tail that is 236 amino acids long and contains nine tyrosine residues. Over two decades ago, Aguado et al.(2002) and Sommers et al.(2002) separately demonstrated that thymic T cell development was impaired in homozygous LAT Y136F knockin mice; these mice also exhibited peripheral lymphoproliferation and rapidly developed an autoimmune phenotype. Tyrosine 136 (tyrosine 132 in human LAT) is required for PLCγ1 recruitment and activation; downstream calcium signaling is abrogated in mutant T cells. It was later shown (Koonpaew et al., 2006) that thymic regulatory T cell (Treg) development is defective in these mice and the ratios of conventional T cells to Tregs in the periphery is very high; this may help explain the broad autoimmune phenotypes seen. Using a single-cell transcriptomic approach, Joachim et al.(2023) serially examined immune cells in the spleens of LAT Y136F mice at different times after birth, and they also used high-dimensional flow cytometry in the spleen and in the lungs to examine T and B cell subsets that infiltrate tissues and are likely drivers of tissue inflammation. TCR levels on T cells in these mice are low and re-triggering of T cells depends heavily on the ligation of CD28. There is an interesting aspect to the cellular changes in these mice that resembles the alterations seen in a set of human inflammatory diseases. The pathological changes of inflammation and fibrosis in these diseases are best attributed to their infiltration by cytotoxic CD4+ T cells (CD4+ CTLs) and activated B cells and also, likely secondarily, CD8+ T cells. CD4+ CTLs were initially studied in the context of viral infection and viral control. These cells were initially implicated in tissue damage, inflammation, and fibrosis in studies on the pathogenesis of an autoimmune disease called IgG4-related disease (IgG4-RD; Mattoo et al., 2016). This disease is characterized by slow-growing inflammatory fibrotic masses in a number of different organs, and by tissue infiltrates of T and B cells. Circulating IgG4 levels are elevated, as are other IgG isotypes, and in many patients, there is elevation in IgE as well. Dramatic clinical improvement is observed within a few weeks after B cell …