The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation.
The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation.
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DOI：
10.1371/journal.pbio.2005046
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发表时间：
2018-09
期刊：
影响因子：
9.8
通讯作者：
Fletcher AL
中科院分区：
文献类型：
--
作者：
Knoblich K;Cruz Migoni S;Siew SM;Jinks E;Kaul B;Jeffery HC;Baker AT;Suliman M;Vrzalikova K;Mehenna H;Murray PG;Barone F;Oo YH;Newsome PN;Hirschfield G;Kelly D;Lee SP;Parekkadan B;Turley SJ;Fletcher AL
淋巴器官的微环境可以通过提供结构和分子支持来帮助健康的免疫功能。在小鼠中，成纤维细胞网状细胞(FRCs)在淋巴结内创造了基本的T细胞支持结构，而人类FRCs在很大程度上是未被研究的。在这里，我们展示了FRC通过4种同时使用的机制在人类外周T细胞激活中创建了一个调节检查点。人类扁桃体和淋巴结来源的FRC抑制了幼稚和预活化T细胞的增殖，使它们的分化偏离了中央记忆T细胞的表型。FRCs通过吲哚胺-2，3-双加氧酶、腺苷2A受体、前列腺素E_2和转化生长因子β受体(TGFR-βR)施加抑制作用，而不需要T细胞反馈。每一种机制途径都是可用药的，针对所有四种机制的抑制剂鸡尾酒完全逆转了FRC的抑制作用。FRCs不能永久性地阻断T细胞，使用嵌合抗原受体(CAR)T细胞的研究表明，在FRCs存在的情况下，免疫治疗性T细胞保留了效应功能。由于小鼠不适合作为概念验证模型，我们开发了一种新的基于人体组织的原位检测方法。在新鲜扁桃体切片中用标准方法刺激的人类T细胞不会增殖，除非在上述抑制剂的存在下。总之，我们定义了一个由四部分组成的分子机制，通过该机制，FRC调节T细胞对次级淋巴器官中强烈激活事件的反应，同时允许激活的和CAR T细胞利用效应器功能。我们的结果确定了4种可行的策略，单独使用或联合使用，通过药理学靶向FRC来增强初级T细胞对感染或癌症的反应。淋巴结微环境包含丰富的免疫细胞，它们与成纤维细胞网状细胞形成的复杂结构框架相互作用，并在其中作用。在小鼠中，已知成纤维细胞网状细胞调节T细胞的激活、增殖和功能，但在人类中，人们对它们知之甚少。我们研究了来自扁桃体和淋巴结的人T细胞和人成纤维细胞网状细胞之间的相互作用。当T细胞在人成纤维细胞网状细胞存在的情况下被激活时，其增殖和分化减少，而不改变效应性T细胞的功能，表现为细胞因子的产生。我们确定了4种分子机制，这些机制是由所有被测试的人成纤维细胞供体同时使用的，并且在共同培养中加入特定的抑制剂后是可逆的。为了确定这一发现与体外共培养的相关性，我们显示了当加入成纤维细胞网状细胞抑制剂时，活体人扁桃体组织切片中T细胞的增殖增加。这项工作表明，人成纤维细胞网状细胞调节T细胞的激活，并提供了关于所用机制的新信息，这可能有助于设计改善T细胞反应的临床策略。
The microenvironment of lymphoid organs can aid healthy immune function through provision of both structural and molecular support. In mice, fibroblastic reticular cells (FRCs) create an essential T-cell support structure within lymph nodes, while human FRCs are largely unstudied. Here, we show that FRCs create a regulatory checkpoint in human peripheral T-cell activation through 4 mechanisms simultaneously utilised. Human tonsil and lymph node–derived FRCs constrained the proliferation of both naïve and pre-activated T cells, skewing their differentiation away from a central memory T-cell phenotype. FRCs acted unilaterally without requiring T-cell feedback, imposing suppression via indoleamine-2,3-dioxygenase, adenosine 2A Receptor, prostaglandin E2, and transforming growth factor beta receptor (TGFβR). Each mechanistic pathway was druggable, and a cocktail of inhibitors, targeting all 4 mechanisms, entirely reversed the suppressive effect of FRCs. T cells were not permanently anergised by FRCs, and studies using chimeric antigen receptor (CAR) T cells showed that immunotherapeutic T cells retained effector functions in the presence of FRCs. Since mice were not suitable as a proof-of-concept model, we instead developed a novel human tissue–based in situ assay. Human T cells stimulated using standard methods within fresh tonsil slices did not proliferate except in the presence of inhibitors described above. Collectively, we define a 4-part molecular mechanism by which FRCs regulate the T-cell response to strongly activating events in secondary lymphoid organs while permitting activated and CAR T cells to utilise effector functions. Our results define 4 feasible strategies, used alone or in combinations, to boost primary T-cell responses to infection or cancer by pharmacologically targeting FRCs. The lymph node microenvironment contains an abundance of immune cells that interact with and within an intricate structural framework created by fibroblastic reticular cells. In mice, fibroblastic reticular cells are known to regulate T-cell activation, proliferation, and function, but in humans, they are poorly understood. We investigated interactions between human T cells and human fibroblastic reticular cells from tonsils and lymph nodes. When T cells were activated in the presence of human fibroblastic reticular cells, their proliferation and differentiation were reduced, without altering effector T-cell function, shown through cytokine production. We identified 4 molecular mechanisms that were responsible, concurrently used by all human fibroblast donors tested, and reversible upon addition of specific inhibitors to the cocultures. To establish the relevance of this finding outside of in vitro coculture, we showed that T-cell proliferation was increased in live human tonsil tissue slices when the fibroblastic reticular cell inhibitors were added. This work demonstrates that human fibroblastic reticular cells regulate T-cell activation and provides new information on the mechanisms used, which may be useful to design clinical strategies that improve T-cell responses.
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