Dissecting the role of virus-specific T cells in providing protection against Marek's Disease Virus in chickens

感染马立克氏病病毒(MDV)会导致鸡的淋巴瘤，每年给全球家禽养殖业造成约15亿GB的损失。每年约有220亿剂MDV疫苗用于控制肿瘤形成，但疫苗未能控制病毒复制，病毒继续进化并形成越来越强的毒株。目前尚不清楚疫苗如何在控制病毒感染的同时控制肿瘤形成。了解疫苗失败的机制(S)对于开发更有效的MDV疫苗至关重要。在动物模型研究中，已表明T淋巴细胞通过产生炎症蛋白、细胞因子及其细胞毒能力参与控制肿瘤形成和病毒感染。在这里，我们的目标是(1)确定产生细胞因子的T淋巴细胞在疫苗接种鸡体内控制肿瘤形成中的作用。(2)检测MDV感染细胞产生的脂质介质PGE2是否抑制感染鸡的T淋巴细胞的细胞毒功能，这可能与疫苗诱导的T细胞反应控制感染失败有关。为了达到这些目标，我们将分析通过将产生细胞因子的T淋巴细胞从接种疫苗的鸡转移到幼稚鸡是否可以控制肿瘤的形成。第二，我们会确定使用PGE2的化学抑制剂和针对病毒蛋白的疫苗接种或过继转移T淋巴细胞是否可以挽救T淋巴细胞的细胞毒功能，从而保护鸡免受肿瘤形成和病毒感染。

Infection with Marek's disease virus (MDV) causes lymphoma in chickens, and is responsible for annual losses of approximately £1.5 billion to the global poultry industry. Approximately 22 billion doses of MDV vaccine are annually used to control tumour formation, but the vaccine fails to control virus replication and the virus continues to evolve and form increasingly virulent strains. It is unknown how the vaccine can control tumour formation whilst failing to control viral infection. Understanding the mechanism(s) involved in vaccine failure is crucial for the development of more effective MDV vaccines.In animal model studies, it has been shown that T lymphocytes are involved in the control of tumour formation and viral infection via production of inflammatory proteins, cytokines, and their cytotoxic abilities. Here, we aim to (1) determine the role of cytokine producing T lymphocytes in the control of tumour formation in vaccinated chickens (2) examine whether a lipid mediator, PGE2, which is produced by MDV infected cells, suppresses cytotoxic function of T lymphocytes in the infected chickens, and this may be involved in the failure of vaccine-induced T cell responses to control infection. To achieve these objectives, we will analyse whether adoptive transfer of cytokine producing T lymphocytes from vaccinated chickens to naïve chickens can control tumour formation. Second, we will determine whether administration of chemical inhibitors of PGE2 and vaccination against viral proteins or adoptive transfer of T lymphocytes can rescue the cytotoxic function of T lymphocytes and thus protects the chickens from both tumour formation and viral infection.