LIGHT_HVEM_BTLA axis in protective anti_viral immunity

描述（由申请人提供）：呼吸道病毒感染是全球第三大死亡原因，也是世卫组织疫苗开发的重点。多年来，科学界一直致力于开发能引起CD8 T细胞反应的治疗性和预防性疫苗，希望这些干预措施足以产生保护作用，并有可能抵消抗病毒反应中抗体部分的任何缺陷。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。出于安全考虑，大多数疫苗接种策略使用复制能力不足或复制能力强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CD8介导的长期保护性免疫方面优于减毒病毒。因此，当试图获得包含减毒载体的真正有效的T细胞疫苗时，降低毒力对免疫原性的影响成为一个中心问题。在本应用中，我们将通过重点研究疫苗病毒（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自然和重组VACV变体，它们调节宿主免疫反应的能力不同，并测试病毒复制水平，受毒力和逃避策略的影响，可以导致CD8 T细胞上必需的激活和抑制受体的差异表达和选择性使用，以允许有效的免疫反应和记忆的持久性。具体来说，我们将验证肺中保护性抗病毒CD8 T细胞反应的产生是由肿瘤坏死因子受体（TNFR）家族成员，疱疹病毒进入介质（HVEM）高度调节的。最近研究发现，HVEM可以通过分别与TNF家族的内源性配体（LIGHT）和Ig样CD28/B7家族的含itim的抑制分子B-和t淋巴细胞衰减剂（BTLA）结合，作为促炎和抑制信号传导之间的分子开关。这两个不同家族之间，特别是共刺激和共抑制受体之间的相互作用，对通过这些相互作用进行免疫调节的确切机制提出了许多新的问题。与这一提议直接相关的是，HVEM与其结合伙伴相互作用在抗病毒反应中的确切作用尚不清楚。通过对表集特异性效应物和记忆CD8 T细胞群在各种交替炎症情况下的表型和功能研究，我们首先提出了产生病毒反应性T细胞群可能需要的LIGHT-HVEM-BTLA相互作用的图像，其次提出了针对这些分子促进长期保护性T细胞记忆抵抗呼吸道病毒感染的基本策略。总的来说，这些研究将为抗病毒CD8 T细胞反应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发展。

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.