Nature报道：重要免疫蛋白的双面人生

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发帖人：marine0425030


Study unlocks basis of key immune protein's two-faced role

由Brigham妇女医院(BWH)领导的一个研究小组，鉴别出了长期以来寻找的、重要免疫蛋白TIM-3的伴侣蛋白，帮助揭示了TIM-3在免疫系统中所扮演的双面角色——有时抑制它，其他时候又刺激它。

由Brigham妇女医院(BWH)领导的一个研究小组，鉴别出了长期以来寻找的、重要免疫蛋白TIM-3的伴侣蛋白，帮助揭示了TIM-3在免疫系统中所扮演的双面角色——有时抑制它，其他时候又刺激它（延伸阅读：Science新闻关注：免疫系统的刹车 ）。

这一最新确认的伴侣蛋白不仅阐明了免疫系统在艾滋病、自身免疫和癌症等一些疾病中的内部运作，还为开发出靶向TIM-3的新疗法提供了一个关键途经。研究人员将他们的研究结果发表在近期的《自然》（Nature）杂志上。

论文的资深作者、Brigham妇女医院胃肠病学、肝脏病学和内窥镜检查部主任Richard Blumberg说：“围绕着TIM-3有许多的困惑——它是如何既抑制又激活免疫系统的。这是一个至关重要的问题，因为TIM-3已被确认为是重要的药物靶点，但由于这一双面特性，没有人真正了解到底要如何处理它。”

人们对于TIM-3作为药物靶点感兴趣主要是源于它的抑制作用，尤其是在癌症之中。当免疫细胞长期受到刺激之时，它们会开启诸如TIM-3一类的信号，帮助它们下调自身的活性。这种称之为“耗竭”（exhaustion）的长期激活状态是HIV 一类的慢性病毒感染的一个免疫标志。它也常见于癌症之中。如果能有一种方法通过药物来阻断TIM-3，就可以释放免疫系统，让其攻击肿瘤。

尽管人们对此感兴趣，但直到现在却仍不了解有关TIM-3作用机制的细节。Blumberg、哈佛医学院Evergrande免疫疾病中心主任Vijay Kuchroo以及同事们，鉴别出了TIM-3的一个关键伴侣蛋白CEACAM-1，CEACAM-1的存在决定了TIM-3将如何起作用。CEACAM-1存在时，TIM-3充当抑制子。CEACAM-1缺乏时，TIM-3则呈现出激活子的特性。

这两种分子协同作用，形成了一个从前未知的全新结构。除了紧密的伙伴关系，它们彼此在结构和功能水平上高度相似。事实上，正是这些相似性最初引导第一作者Yu-Hwa Huang提出，CEACAM-1是长期以来寻找的TIM-3伴侣蛋白。

利用各种方法，Blumberg和他的研究小组设法揭示出了CEACAM-1的作用本质。重要的是，他们发现在大肠癌小鼠模型中一些缺失CEACAM-1的工程免疫细胞显示炎症增加，同时阻断CEACAM-1和TIM-3可以增强抗肿瘤反应。

Blumberg说：“令人感到兴奋之处在于，我们的数据告诉了我们如何来靶向TIM-3。其真正为我们指出了一条途经，如何开发出针对癌症和艾滋病等其他疾病的一种全新治疗范式。”

本资料来源于生物通 www.ebiotrade.com

原文摘要

CEACAM1 regulates TIM-3-mediated tolerance and exhaustion
T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers1, 2, 3, 4, 5. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition6, 7, 8, 9, 10. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.


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F1000 Microbiology
University of Tennessee, Knoxville, TN, USA.

NEW FINDING
DOI: 10.3410/f.725223775.793501268
An increasing number of disease circumstances appear to be the consequence of poorly performing (often called exhausted) T cells. Fortunately, poor performance is correctable if the mechanisms responsible are blunted, but all of the players involved are yet to be identified. The present paper by Blumberg and colleagues adds further mechanistic understanding of underachieving T cells. It shows that the molecule TIM-3, already advocated as involved in mediating exhaustion, is controlled by a second molecule CEACAM-1 formerly linked to T cell regulation {1}. The new results show that TIM-3 expression and its inhibitory function are controlled by interacting with CEACAM-1. Moreover, the co-blockage of both molecules was more effective in delaying tumor growth in a mouse model of colorectal cancer than could be achieved by blocking TIM-3 alone. Already, there is clinical evidence that co-blockade of PD-1 and CTLA-4 is useful to control some tumors. It could be that additionally manipulating the CEACAM-1/TIM-3 interaction might provide an even more effective means of resurrecting T cell poor performance.
References
1.Activation-induced expression of carcinoembryonic antigen-cell adhesion molecule 1 regulates mouse T lymphocyte function.
Nakajima A, Iijima H, Neurath MF, Nagaishi T, Nieuwenhuis EE, Raychowdhury R, Glickman J, Blau DM, Russell S, Holmes KV, Blumberg RS. J Immunol 2002 Feb 1; 168(3):1028-35
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