LIGHT_HVEM_BTLA axis in protective anti_viral immunity

描述（由申请方提供）：呼吸道病毒感染是全球第三大死亡原因，是世卫组织疫苗开发的优先事项。多年来，科学界已经将巨大的努力集中在开发引发CD 8 T细胞应答的治疗性和预防性疫苗上，并承诺这种干预将足以赋予保护作用并潜在地抵消抗病毒应答的抗体臂中的任何缺陷。然而，迄今为止，针对呼吸道病毒的有效T细胞疫苗的开发仍然难以捉摸。出于安全性原因，大多数疫苗接种策略使用无复制能力或有复制能力的高度减毒病毒载体。然而，有相当多的文献承认，强复制病毒在诱导长期保护性CD 8介导的免疫方面比减毒病毒更好。因此，当试图获得掺入减毒载体的真正有效的T细胞疫苗时，降低的毒力对免疫原性的影响成为中心问题。在本申请中，我们将通过关注疫苗病毒（VACV）来研究区分减毒疫苗和非减毒疫苗的分子基础。我们将使用几种临床相关的天然和重组VACV变体，它们调节宿主免疫应答的能力不同，并测试病毒复制水平受毒力和逃避策略影响的想法，可以导致CD 8 T细胞上必需的活化和抑制受体的差异表达和选择性使用，以允许有效的免疫应答和记忆的持久性。具体来说，我们将测试的想法，即在肺中的保护性抗病毒CD 8 T细胞反应的产生是高度调节的肿瘤坏死因子受体（TNFR）家族成员，疱疹病毒进入介质（HVEM）。最近发现HVEM可通过分别与来自TNF家族的内源性配体（LIGHT）和来自IG样CD 28/B7家族的含ITIM的抑制性分子B-和T-淋巴细胞衰减剂（BTLA）结合而在促炎和抑制性信号传导之间充当分子开关。这两个不同家族之间的串扰，特别是共刺激和共抑制受体之间的串扰，提出了许多新的问题，关于通过这些相互作用进行免疫调节的精确机制。与该提议直接相关的是，HVEM与其结合伴侣在抗病毒应答中相互作用的精确贡献尚不清楚。通过在各种交替炎症的情况下进行表位特异性效应子和记忆CD 8 T细胞群体的表型和功能研究，我们首先提出制定可能需要产生病毒反应性T细胞群体的LIGHT-HVEM-BTLA相互作用的图片，其次，制定一个合理的战略，针对这些分子，以促进长期-长期保护性T细胞记忆对抗呼吸道病毒感染。总的来说，这些研究将为抗病毒CD 8 T细胞应答的发展提供新的见解，并促进新型佐剂和疫苗策略的转化研究开发。 公共卫生相关性：许多病毒利用呼吸道作为进入宿主的入口。呼吸道病毒感染是全世界发病率和死亡率的主要原因。了解保护性抗病毒CD 8 T细胞免疫是如何调节的，对于设计更安全，更有效的T细胞疫苗来对抗呼吸道病原体以及管理与免疫病理学相关的不良免疫反应至关重要。

DESCRIPTION (provided by applicant): Respiratory viral infections are the third leading cause of death worldwide and are a WHO priority for vaccine development. For many years the scientific community has focused enormous efforts on the development of therapeutic and prophylactic vaccines that elicit CD8 T cell responses with the promise that such interventions will be sufficient to confer protective effects and potentially offset any deficiency in the antibody arm of the anti- viral response. However, to date the development of effective T cell vaccines against respiratory viruses remains elusive. For safety reasons, most vaccination strategies use replication-incompetent, or replication competent highly attenuated, viral vectors. However, there is considerable literature acknowledging that strongly replicating viruses are better at inducing long-term protective CD8 mediated immunity than attenuated viruses. Therefore, the effect of reduced virulence on immunogenicity becomes a central issue when attempting to derive a truly effective T cell vaccine that incorporates attenuated vectors. In this application, we will investigate the molecular basis that differentiates attenuated from non-attenuated vaccines by focusing on vaccine virus (VACV). We will use several clinically relevant natural and recombinant VACV variants that differ in their ability to modulate host immune responses and test the idea that the level of virus replication, influenced by virulence and evasion tactics, can lead to differential expression and selective use of essential activating and inhibitory receptors on CD8 T cells, to allow efficient immune responses and persistence of memory. Specifically, we will test the idea that generation of protective anti-viral CD8 T cell responses in the lung are highly regulated by the tumor-necrosis-factor receptor (TNFR) family member, herpes virus-entry mediator (HVEM). Recently it was found that HVEM could act as a molecular switch between pro inflammatory and inhibitory signaling by respectively binding with its endogenous ligand (LIGHT) from the TNF family and ITIM-containing inhibitory molecule B- and T-lymphocyte attenuator (BTLA) from the Ig like CD28/B7 family. The crosstalk between these two different families and especially between co-stimulatory and co-inhibitory receptors has raised many new questions with regards to the precise mechanisms of immune modulation through these interactions. Directly relevant to this proposal, the precise contribution of HVEM interacting with its binding partners in anti-viral responses is unknown. By performing phenotypic and functional studies of epitome-specific effectors and memory CD8 T cell populations in various situations of alternate inflammation, we propose firstly to formulate a picture of the LIGHT-HVEM-BTLA interactions that may be required to generate a virus-reactive T cell population, and secondly to formulate a rationale strategy for targeting these molecules to promote long-term protective T cell memory against respiratory viral infections. Collectively, these studies will provide new insight into the development of anti-viral CD8 T cell responses and facilitate the translational research development of novel adjuvant and vaccine strategies. PUBLIC HEALTH RELEVANCE: Many viruses utilize the respiratory tract as an entry point into the host. Respiratory viral infections are the major cause of morbidity and mortality throughout the world. Understanding how protective anti-viral CD8 T cell immunity is regulated is essential for designing safer and more effective T cell vaccines to combat respiratory pathogens and in the management of adverse immune reactions associated with immune pathology.