Identifying the role of 4-1BB in generation and persistence of VACV-CD8 memory

描述(申请人提供)：痘苗病毒(VACV)对天花的媒介天花病毒具有持久的保护作用。VACV特异的CD8记忆T细胞有助于保护，但其分子控制尚不完全清楚。本研究的目的是确定和了解肿瘤坏死因子受体家族成员4-1BB在控制内源性VACV特异性记忆性CD8 T细胞的产生和持续中的作用，并研究靶向该分子是否可以增强多肽或减毒病毒免疫的效力，以保护其免受后续感染。VACV正被用作针对多种传染病病原体的疫苗接种载体，从我们的研究中获得的知识有望有助于开发包含VACV载体的安全而有效的疫苗。野生型、减毒和重组痘苗病毒包含一个明确的CD8T细胞表位的卵蛋白(OVA)，将用于缺乏4-1BB或4-1BBL的敲除动物的实验，以显示它们在产生VACV特异性CD8T细胞方面的贡献。此外，TCR转基因CD8 T细胞，与VACV-OVA反应，缺乏4-1BB，将通过跟踪体内过继转移的T细胞来明确4-1BB在T细胞上的作用。激动剂试剂4-1BB，单独或与其他各种佐剂联合使用，将研究能否诱导保护性T细胞群，从而中和致死性感染。这项研究应该为4-1BB在控制VACV的T细胞反应中的重要性提供宝贵的数据，并强调它作为未来疫苗接种策略的目标的潜在作用。 公共卫生相关性：痘苗病毒(VACV)对天花的病原体天花病毒具有持久的保护作用。这项研究旨在了解有助于保护病毒的病毒特异性CD8记忆T细胞的分子控制。这项研究将有助于开发更好的VACV传染病疫苗和癌症免疫治疗。

DESCRIPTION (provided by applicant): Vaccinia virus (VACV) affords long-lasting protection against variola virus, the agent of smallpox. VACV- specific CD8 memory T cells contribute to protection but their molecular control is not fully understood. The goal of the current project is to identify and understand the role of 4-1BB, a member of the TNF receptor family, in controlling the generation and persistence of endogenous VACV-specific memory CD8 T cells, and to investigate whether targeting this molecule can enhance the efficacy of peptide or attenuated virus immunization to protect against subsequent infection. VACV is being used as a vector for vaccination against a wide range of infectious pathogens and knowledge gained from our studies will hopefully aid the development of safe but effective vaccines comprising VACV vectors. Wild type, attenuated, and recombinant vaccinia virus, containing a defined CD8 T cell epitope of ovalbumin (OVA), will be used in experiments with knockout animals lacking 4-1BB or 4-1BBL to show their contribution in generating VACV-specific CD8 T cells. Additionally, TCR transgenic CD8 T cells, reactive with VACV-OVA, and deficient in 4-1BB, will be used to specifically define the role of 4-1BB on a T cell by tracking adoptively transferred T cells in vivo. Agonist reagents to 4-1BB, alone or in combination with various other adjuvants, will be studied in terms of eliciting protective T cell populations that can neutralize lethal infections. This research should provide invaluable data on the importance of 4-1BB in controlling T cell responses to VACV and highlight its potential role as a target for future vaccination strategies. PUBLIC HEALTH RELEVANCE: Vaccinia virus (VACV) affords long-lasting protection against variola virus, the agent of smallpox. This research aims to understand the molecular control of virus-specific CD8 memory T cells that contribute to protection. This study will benefit the development of better VACV vaccines for infectious diseases as well as cancer immunotherapy.