The role of CCR8 in cutaneous vaccination

CCR8在皮肤疫苗接种中的作用

• 批准号: MR/L018284/1
• 负责人: Bernhard Moser
• 金额: $ 73.65万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL018284%2F1
• 关键词: role; CCR8; cutaneous; vaccination

Our immune system fights microbes, such as bacteria, viruses, and tumours by rapidly activating immune cells, which then kill infected tissue cells and tumour cells in a highly specific manner. In an initial response, effector lymphocytes (T cells) quickly reach the site of infection and tumours where they recognize and kill these targets. Later, an immune memory compartment, composed of lymphocytes sharing the specificity of the primary effector lymphocytes, is established in order to provide long-lasting protection against the same challenges. Similarly, tolerance-inducing memory T (Treg) cells are established to prevent unwanted immunity at discrete tissue locations. Under normal circumstances, memory T cells are known to reside in healthy peripheral tissues, such as skin, lungs and the digestive-urinary tracts (herein referred to as peripheral immune surveillance T [TPS] cells), where they wait for a new attack by the same infectious particles or tumour cells. This cellular immune surveillance system is at the heart of vaccination, a process whereby microbe-specific long-lived memory T and B cells are generated to establish a first-line defense against harmful infections. Smallpox vaccination, for instance, can be considered as one of the most successful examples of skin vaccination that led to world-wide eradication of a deadly infectious disease. It is clear that TPS cells present in peripheral tissues make up a vast immune memory compartment that protects body surfaces from recurrent infections and autoimmune diseases. Human skin, for instance, harbours twice as many T cells as the combined T cells present in peripheral blood. Although we know much about immune cells present in peripheral blood, our knowledge about peripheral tissue TPS cells is rudimentary. Our lack of understanding is due in part to technical difficulties (access of healthy tissue, cell isolation) when working with TPS cells, which is not the case when working with peripheral blood T cells. Thanks to established collaboration with numerous plastic surgeons, we have been studying TPS cells present in healthy human skin. Our recent work has demonstrated that the majority of human skin TPS cells express the chemokine receptor CCR8, suggesting that CCR8 is involved in the recruitment and/or retention of TPS cells in healthy skin. Preliminary data indicate that T cells in other (skin-unrelated) tissues do not express CCR8, which led us to propose that CCR8 is a selective marker for cutaneous TPS cells. We hypothesize that CCR8+ TPS cells are generated in response to cutaneous vaccination. To test this hypothesis we will turn to mouse models of cutaneous vaccination using the model antigen OVA (ovalbumin) and well defined OVA-specific T cells. Obviously, such studies cannot easily be carried out in humans. In brief, the proposed mouse studies will reveal when in response to vaccination T cells start to express CCR8, which may occur at the early stage of an immune response when short-lived effector T cells predominate or at a late stage when the immune response has resolved and long-lived memory T cells have emerged. We will also find out where (skin tissue or skin-draining lymph nodes) CCR8+ T cells are formed. Ultimately, these studies are essential for understanding the importance of CCR8 and its chemokines in the generation and maintenance of the skin-specific immune surveillance system.

我们的免疫系统通过快速激活免疫细胞来对抗细菌，病毒和肿瘤等微生物，然后以高度特异性的方式杀死受感染的组织细胞和肿瘤细胞。在最初的反应中，效应淋巴细胞（T细胞）迅速到达感染和肿瘤部位，在那里它们识别并杀死这些靶点。随后，建立由共享初级效应淋巴细胞特异性的淋巴细胞组成的免疫记忆区室，以提供针对相同挑战的持久保护。类似地，建立耐受诱导记忆T（Treg）细胞以防止在离散组织位置处的不需要的免疫。在正常情况下，已知记忆T细胞存在于健康的外周组织中，例如皮肤，肺和消化道-泌尿道（本文称为外周免疫监视T [TPS]细胞），在那里它们等待相同感染性颗粒或肿瘤细胞的新攻击。这种细胞免疫监视系统是疫苗接种的核心，这是一个产生微生物特异性长寿记忆T和B细胞的过程，以建立对抗有害感染的第一线防御。例如，天花疫苗接种可以被认为是皮肤疫苗接种的最成功的例子之一，它导致了世界范围内的致命传染病的根除。很明显，存在于外周组织中的TPS细胞构成了一个巨大的免疫记忆区室，保护身体表面免受复发性感染和自身免疫性疾病的侵害。例如，人类皮肤中T细胞的数量是外周血中T细胞总数的两倍。虽然我们知道很多关于免疫细胞存在于外周血，我们的知识外周组织TPS细胞是基本的。我们缺乏理解的部分原因是在使用TPS细胞时存在技术困难（健康组织的获取，细胞分离），而在使用外周血T细胞时并非如此。由于与众多整形外科医生建立了合作关系，我们一直在研究健康人体皮肤中存在的TPS细胞。我们最近的工作表明，大多数人皮肤TPS细胞表达趋化因子受体CCR 8，这表明CCR 8参与健康皮肤中TPS细胞的募集和/或保留。初步数据表明，其他（皮肤无关）组织中的T细胞不表达CCR 8，这使我们提出CCR 8是皮肤TPS细胞的选择性标志物。我们假设CCR 8 + TPS细胞是在皮肤接种后产生的。为了检验这一假设，我们将转向使用模型抗原OVA（卵清蛋白）和明确定义的OVA特异性T细胞的皮肤接种的小鼠模型。显然，这样的研究不容易在人类身上进行。简而言之，所提出的小鼠研究将揭示何时响应于疫苗接种T细胞开始表达CCR 8，这可能发生在免疫应答的早期阶段，当短寿命效应T细胞占主导地位时，或者发生在免疫应答已经消退并且长寿命记忆T细胞已经出现的晚期阶段。我们还将发现CCR 8 + T细胞在哪里（皮肤组织或皮肤引流淋巴结）形成。最终，这些研究对于理解CCR 8及其趋化因子在皮肤特异性免疫监视系统的产生和维持中的重要性至关重要。

项目成果

CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems.

• DOI: 10.3389/fimmu.2020.561404
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Kouzeli A;Collins PJ;Metzemaekers M;Meyrath M;Szpakowska M;Artinger M;Struyf S;Proost P;Chevigne A;Legler DF;Eberl M;Moser B
• 通讯作者: Moser B

CCR8 Expression Defines Tissue-Resident Memory T Cells in Human Skin.

• DOI: 10.4049/jimmunol.1701377
• 发表时间: 2018-03-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: McCully ML;Ladell K;Andrews R;Jones RE;Miners KL;Roger L;Baird DM;Cameron MJ;Jessop ZM;Whitaker IS;Davies EL;Price DA;Moser B
• 通讯作者: Moser B

Editorial: History of Chemoattractant Research.

• DOI: 10.3389/fimmu.2015.00548
• 发表时间: 2015
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Moser B

Skin Metabolites Define a New Paradigm in the Localization of Skin Tropic Memory T Cells.

• DOI: 10.4049/jimmunol.1402961
• 发表时间: 2015-07-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: McCully ML;Collins PJ;Hughes TR;Thomas CP;Billen J;O'Donnell VB;Moser B
• 通讯作者: Moser B

Chemokine Receptor-Targeted Therapies: Special Case for CCR8.

• DOI: 10.3390/cancers14030511
• 发表时间: 2022-01-20
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Moser B