T细胞受体的秘密生活及其在免疫反应中的作用

StephenW

The secret lives of T cell receptors and their role in the immune response

by Delthia Ricks , Medical Xpress
Credit: CC0 Public Domain

Canadian immunologists have identified a mechanism that promotes the activation of T cell receptors by altering how one of its components interacts with the cell membrane.

The finding sheds new light on the function of T cell receptors, illuminating the role of specific proteins in the cell membrane.

Up close, the T cell receptor is a cluster of proteins on the surface of T cells that bind to antigens—foreign proteins—displayed on abnormal cells, such as cancer cells or those infected with bacteria or viruses. T cell interaction with abnormal cells is a major strategy in which the immune system mounts its assault on infection, cancer, and other diseases.

As a key multi-protein complex, the T cell receptor is critical for the activation of T cells by antigens. And T cells themselves are capable of forming memories of antigens, which means upon reexposure, T cells can more rapidly respond to a familiar enemy.

Immunologists at two leading Canadian research centers, the Institut de Recherche en Immunologie et Cancérologie and the Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, embarked on the laboratory investigations to more fully grasp the intricate function of T cell receptors—and T cells themselves. In the end, they broke new ground, adding to the overall understanding of these cells and their storied receptors.

The new findings arrive as an increasingly bright spotlight has been trained on T cell activation, T cell binding and the role these key immune system cells play after vaccination for COVID-19. Beyond the Canadian team's research, the subjects of T cell activation and T cell receptor biology have captured the public's attention in the wake of the pandemic. Discussions in the popular press and social media have frequently explored whether COVID vaccination prompts memory T cell activity and a strong T cell response against SARS-CoV-2. The Montréal research has laid a new foundation of understanding for both the scientific and lay communities.

"We investigated how the electrostatic interactions that promote dynamic membrane binding of the T cell receptor-CD3 cytoplasmic domains are modulated during signaling and affect T cell activation," Drs. Audrey Connolly and Etienne Gagnon wrote in the journal Science Signaling.

What they discovered were the critical key steps in how T cell receptor signaling is enhanced in a chain of biological events that result in the activation of T cells. The T multiprotein receptor is critical to the activation of T cells by antigens—any foreign substance that induces an immune response in the body. Although the engagement of T cell receptors by antigens activates T cell receptor signaling, T cell receptors that are not bound to antigens also can become activated and contribute to T cell activation, the team of immunologists found. T cell receptors that are not bound to antigens are called bystanders. These bystander T cell receptors serve to amplify T cell signaling.

To fully appreciate the research by the Canadian team of immunologists, it is necessary to delve into the "weeds" of structural, molecular and cellular biology to picture where these activities are physically occurring and why they are important to the immune response and other biological functions. The drama of cell signaling emanates from the surface of cells.

All cells are enclosed in the so-called plasma membrane, a thin border that surrounds every living cell. The membrane itself is made up of a lipid bilayer—two layers of phospholipids. Although this border is what maintains the integrity of cells and prevents their contents from flowing out, the plasma membrane has the consistency of olive oil. Each phospholipid bilayer is known as a "leaflet."

The membrane as a whole is home to transmembrane proteins that are embedded in it, some protruding above the surface. Some transmembrane proteins are capable of powerful signaling activities. Channels are also in the membrane allowing the flow of ions into and out of the cell.

The Montréal immunologists were interested in a transmembrane protein from a key superfamily of transmembrane constituents—transmembrane protein 16F, or THEM16F, which is crucial to T cell activation because it aids signal amplification by the T cell receptor. The THEM16 superfamily is a calcium ion-dependent phospholipid scramblase.

Scramblases, control the distribution and composition of phospholipids within the bilayer, which has important effects on the functions of membrane proteins, by swapping phospholipids between the two leaflets.

Conolly and Gagnon found, for instance, that the scramblase TMEM16F, which redistributes phosphatidylserine from the inner to the outer leaflet of the plasma membrane, enabled CD3 cytoplasmic domains of bystander T cell receptors to disengage from the plasma membrane, leading to enhanced T cell activation. The CD3 cluster is a protein complex and T cell co-receptor involved in activating cytotoxic T cells and T helper cells.

These bystanders were in the vicinity of antigen-stimulated T cell receptors and served to amplify T cell signaling. Targeting TMEM16F therapeutically may enable modulation of T cell activation, the Montréal immunologists theorize.

In addition to playing a role in T cell activation, THEM16F also mediates the exposure of the phospholipid known as phosphatidylserine in activated platelets during blood clotting and regulates hydroxyapatite release from osteoblasts during bone mineralization. But it is the role in T cell activation that Connolly, Gagnon and colleagues sought to elucidate.

"This study establishes the molecular basis for the role of TMEM16F in bystander T cell receptor-induced signal amplification and identifies enhancement of TMEM16F function as a potential therapeutic strategy for promoting T cell activation," Connolly and Gagnon concluded.

StephenW

T细胞受体的秘密生活及其在免疫反应中的作用

医疗快讯Delthia Ricks
信用：CC0公共领域

加拿大的免疫学家已经确定了一种机制，该机制可通过改变其成分之一与细胞膜的相互作用来促进T细胞受体的活化。

这一发现为T细胞受体的功能提供了新的思路，阐明了特定蛋白在细胞膜中的作用。

最近，T细胞受体是T细胞表面上与抗原（外源蛋白质）结合的蛋白质簇，这些抗原显示在异常细胞（例如癌细胞或感染细菌或病毒的细胞）上。 T细胞与异常细胞的相互作用是免疫系统对感染，癌症和其他疾病发起攻击的主要策略。

作为关键的多蛋白复合物，T细胞受体对于抗原激活T细胞至关重要。 T细胞本身能够形成抗原记忆，这意味着在再次暴露后，T细胞可以更快地对熟悉的敌人做出反应。

加拿大两个主要研究中心的免疫学家，坎昆法医学研究所和蒙特利尔微生物学院的微生物学传染病学与免疫学部门，着手进行实验室研究，以更全面地掌握T细胞受体的复杂功能。 -和T细胞本身。最后，它们开辟了新天地，使人们对这些细胞及其存储的受体有了更全面的了解。

随着对T细胞活化，T细胞结合以及在接种COVID-19疫苗后这些关键免疫系统细胞所起的作用受到越来越多的关注，新的发现得以实现。除了加拿大研究小组的研究之外，大流行之后T细胞活化和T细胞受体生物学的研究也引起了公众的关注。流行媒体和社交媒体上的讨论经常探讨COVID疫苗接种是否能促进记忆性T细胞活性以及对SARS-CoV-2的强烈T细胞反应。蒙特利尔的研究为科学界和外行社区奠定了新的理解基础。

“我们研究了在信号传导过程中如何调节促进T细胞受体CD3细胞质域动态膜结合的静电相互作用，并影响T细胞活化。”奥黛丽·康诺利（Audrey Connolly）和艾蒂安·加农（Etienne Gagnon）在《科学信号》杂志上撰文。

他们发现的是在一系列导致T细胞活化的生物学事件中如何增强T细胞受体信号传导的关键关键步骤。 T多蛋白受体对于抗原激活T细胞至关重要-抗原是在体内诱导免疫反应的任何异物。免疫学家小组发现，尽管抗原与T细胞受体的结合可以激活T细胞受体的信号传导，但未与抗原结合的T细胞受体也可以被激活并有助于T细胞激活。未与抗原结合的T细胞受体称为旁观者。这些旁观者T细胞受体用于扩增T细胞信号传导。

为了完全理解加拿大免疫学家团队的研究，有必要深入研究结构，分子和细胞生物学的“杂草”，以描绘这些活动在物理上发生的位置以及它们为什么对免疫应答和其他生物学功能很重要。细胞信号传递的戏剧性起源于细胞表面。

所有细胞都被包封在所谓的质膜中，质膜围绕着每个活细胞。膜本身由脂质双层（两层磷脂）组成。尽管此边界可保持细胞的完整性并防止其内容物流出，但质膜具有橄榄油的稠度。每个磷脂双层被称为“小叶”。

整个膜是嵌入膜中的跨膜蛋白的宿主，其中一些膜突出到表面上方。一些跨膜蛋白具有强大的信号转导活性。通道也位于膜中，允许离子流入和流出细胞。

蒙特利尔的免疫学家对跨膜成分的重要超家族跨膜蛋白-跨膜蛋白16F或THEM16F感兴趣，这对T细胞活化至关重要，因为它有助于T细胞受体进行信号放大。 THEM16超家族是钙离子依赖性磷脂加扰酶。

Scramblases通过在两个小叶之间交换磷脂来控制双层中磷脂的分布和组成，这对膜蛋白的功能具有重要影响。
例如，Conolly和Gagnon发现，乱序酶TMEM16F从质膜的内部向外部小叶重新分配磷脂酰丝氨酸，使旁观者T细胞受体的CD3细胞质结构域脱离质膜，从而导致增强的T细胞活化。 CD3簇是一种蛋白质复合物和T细胞共受体，参与激活细胞毒性T细胞和T辅助细胞。

这些旁观者在抗原刺激的T细胞受体附近，并用于放大T细胞信号传导。蒙特利尔免疫学家认为，治疗性靶向TMEM16F可能可以调节T细胞活化。

除了在T细胞活化中起作用外，THEM16F还可以在凝血过程中介导活化血小板中磷脂（称为磷脂酰丝氨酸）的暴露，并在骨骼矿化过程中调节成骨细胞中羟磷灰石的释放。但是，Connolly，Gagnon及其同事试图阐明的是T细胞活化中的作用。

Connolly和Gagnon总结说：“这项研究为TMEM16F在旁观者T细胞受体诱导的信号放大中的作用建立了分子基础，并确定TMEM16F功能的增强是促进T细胞活化的潜在治疗策略。”