The role of CCR8 in cutaneous vaccination

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，然后免疫细胞以高度特异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，在那里他们识别和杀死这些靶点。后来，由具有初级效应淋巴细胞的特异性的淋巴细胞组成的免疫记忆隔间被建立，以提供针对相同挑战的长期保护。同样，耐受性诱导记忆T(Treg)细胞的建立是为了防止在离散组织位置产生不必要的免疫。在正常情况下，已知记忆T细胞存在于健康的外周组织中，如皮肤、肺和消化-尿路(这里称为外周免疫监视T[TPS]细胞)，在那里它们等待相同的感染颗粒或肿瘤细胞的新攻击。这种细胞免疫监控系统是疫苗接种的核心，通过这个过程，微生物特有的长寿记忆T和B细胞被产生，以建立针对有害感染的一线防御。例如，天花疫苗可以被认为是皮肤疫苗接种导致世界范围内根除一种致命传染病的最成功的例子之一。很明显，存在于周围组织中的TPS细胞构成了一个巨大的免疫记忆隔间，保护身体表面免受反复感染和自身免疫性疾病的侵袭。例如，人类皮肤中含有的T细胞是外周血中组合T细胞的两倍。虽然我们对外周血中存在的免疫细胞了解很多，但我们对外周组织TPS细胞的了解还很初级。我们缺乏了解的部分原因是在处理TPS细胞时的技术困难(获取健康组织、细胞分离)，而在处理外周血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CCR8，这表明CCR8参与了TPS细胞在健康皮肤中的募集和/或滞留。初步数据表明，其他(皮肤无关)组织中的T细胞不表达CCR8，这使得我们认为CCR8是皮肤TPS细胞的选择性标记物。我们假设CCR8+TPS细胞是在皮肤接种后产生的。为了验证这一假设，我们将转向使用模式抗原OVA(卵清蛋白)和明确定义的OVA特异性T细胞进行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，拟议的小鼠研究将揭示T细胞在接种疫苗后何时开始表达CCR8，这可能发生在免疫反应的早期阶段，当短期效应T细胞占主导地位时，或者发生在免疫反应已经消失并出现长期记忆T细胞的晚期阶段。我们还将找出(皮肤组织或皮肤引流淋巴结)CCR8+T细胞是在哪里形成的。最终，这些研究对于理解CCR8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。

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.