Crossreactivity of T Cells In Human Virus Infections

全面了解与产生和调节相关的机制， 免疫T细胞记忆将有助于更好地理解免疫系统如何控制病毒， 感染，但也导致免疫介导的病理。异源性免疫， 不相关病原体之间的T细胞交叉反应性（XR），例如甲型流感（IAV），牛痘病毒， 沙粒病毒和鼠巨细胞病毒，已经被我们用动物模型证明有助于 减少（有益）或增强病毒载量，并显著改变免疫病理学（有害）。我们 已经证明了在人类感染EB病毒（EBV）中的异源免疫，而其他研究表明， 研究人员已经证明了它在流感、登革热和丙型肝炎病毒中的作用。我们已经确定 在HLA-A2+急性淋巴细胞白血病患者中与EBV-BMLFI 280相互作用的交叉反应性T细胞网络 传染性单核细胞增多症（AIM），并直接相关的严重程度与记忆的频率 甲型流感缺失特异性CD 8 T细胞与EBV-表位交叉反应。交叉反应的所有功能 似乎比单独对任一抗原的非交叉反应性库更广。我们在五分钟内有证据 EBV-血清阴性健康供体表明IAV Ml-特异性应答和IAV Ml-特异性应答之间的独特交叉反应性。 EBV抗原表位可能具有保护性。这项研究的主要目的是确定T细胞是如何跨- 反应性影响T细胞的选择和功能，并改变疾病结果，无论好坏，因为 宿主暴露于随后的急性或持续性感染，如EBV。对这些问题的见解是 这对于智能设计有效且无不良副作用的现代疫苗是必要的 并在病毒感染诱导免疫病理学时开发治疗干预。我们是一 一些研究病毒系统中异源免疫的小组，并建议在 以下目标：1）检查控制保护性免疫与 EBV感染期间异源免疫的病理学; 2）检查XR TcR谱系如何影响 异源保护性免疫和免疫病理学; 3）测试老年人具有 由于异源感染而增加的交叉反应性应答。 相关性（参见说明）： 这些研究解决了与公共卫生相关的问题，例如能否设计出成功的T细胞疫苗 在什么情况下病毒会引起严重的病理 有没有办法绕过它这些研究为个性化的发展开辟了新的途径 如果鉴定出交叉反应性表位，则用于治疗和疫苗，或者如果不存在交叉反应性表位，则用于广谱治疗。

A comprehensive understanding of the mechanisms associated with the generation and modulation of immunological T cell memory will lead to a better understanding of how the immune system controls viral infections but also causes immune-mediated pathology. Heterologous immunity occurring as a consequence of T cell cross-reactivity (XR) between unrelated pathogens, such as influenza A (lAV), vaccinia virus, arenaviruses, and murine cytomegalovirus, has been shown by us with animal models to contribute to reduced (beneficial) or enhanced viral loads, and remarkably altered immunopathology (detrimental). We have demonstrated heterologous immunity in human infections with Epstein-Barr virus (EBV), while other investigators have demonstrated its role in influenza, dengue, and hepatitis C viruses. We have identified networks of cross-reactive T cells, which interact with EBV-BMLFI280 in HLA-A2+ patients with acute infectious mononucleosis (AIM) and directly correlated the severity of AIM with the frequency of memory influenza A Miss-specific CD8 T cells cross-reactive with EBV-epitopes. The cross-reactive repertoire appears broader than the non-cross-reactive repertoire to either antigen alone. We have evidence in five EBV-seronegative healthy donors that a unique cross-reactivity between lAV Ml-specific responses and EBV epitopes maybe protective. The overall objective of this proposal is to determine how T cell cross- reactivity impacts T cell selection and function, and changes disease outcome, to the worse or better, as the host is exposed to subsequent acute or persistent infections such as EBV. Insights on these issues are necessary for the intelligent design of modern vaccines that are effective and without unwanted side effects and to develop therapeutic interventions when virus infection induces immunopathology. We are one of the few groups studying heterologous immunity in viral systems and propose to clarify these issues in the following aims: 1) examine the mechanisms which control the balance between protective immunity versus pathology in heterologous immunity during EBV infection; 2) examine how XR TcR repertoires influence heterologous protective immunity and immunopathology; 3) test the hypothesis that elderly individuals have increased crossreactive responses due to heterologous infections. RELEVANCE (See instructions): These studies address public health-relevant questions such as can one design successful T cell vaccines that will give protection without pathology and under what circumstances do viruses induce severe pathology and are there ways to circumvent it? These studies open new avenues for the development of individualized therapies and vaccines if cross-reactive epitopes are identified or broad spectrum therapy in their absence.