Selection of inflationary and tissue-resident T cells during MCMV infection

MCMV 感染期间膨胀和组织驻留 T 细胞的选择

• 批准号: 8651139
• 负责人: Christopher M Snyder
• 金额: $ 18.21万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651139
• 关键词: Affinity; Antigens; Blood Circulation; Bone Marrow; Cells; Chimera organism; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Disease; Economic Inflation; Environment; Epithelium; Equilibrium; Face; Fetus; Genes; Gland; Goals; Growth; HIV; Herpesviridae; Herpesviridae Infections; Human; Human Milk; Immune; Immunity; Immunodominant Antigens; Immunologic Surveillance; Infection; Institute of Medicine (U.S.); Integrins; Knowledge; Life; Maintenance; Malignant Neoplasms; Mammary gland; Measures; Memory; Modeling; Mucous Membrane; Mus; OVA-8; Ovalbumin; Population; Positioning Attribute; Predisposition; Pregnant Women; Process; Role; Salivary Glands; Series; Site; Spleen; Surface; Systemic infection; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Vaccine Design; Vaccines; Variant; Viral; Viral Antigens; Virus; Virus Latency; Virus Shedding; Work; cytokine; emergency service responder; mucosal site; novel; novel vaccines; pathogen; pressure; prevent; public health relevance; pup; reactivation from latency; recombinant virus; research study; therapy design; tool; transmission process

Abstract: Cytomegalovirus (CMV) is a ubiquitous herpesvirus that establishes a systemic, persistent infection. CMV rarely causes serious disease in humans because systemic, life-long immune surveillance keeps the virus in check. In fact, CMV stimulates the largest known T cell populations in the circulation of humans. These T cells accumulate over time in a process called "memory inflation" and control CMV by shutting down viral reactivation from latency. For these reasons, CMV may serve as a tool for new vaccines against diseases such as cancer and HIV. However, CMV can cause devastating disease in a developing fetus when the virus is transmitted to a pregnant woman. Thus, a vaccine to prevent CMV transmission is rated as a highest priority by the Institute of Medicine. Understanding immune surveillance at sites of viral shedding will be key to preventing transmission and CMV disease. Recent work has shown that a T cell population called "resident memory" T cells (TRM) are established at sites in the body that may face viral reactivation. Indeed, TRM cells may help control herpesvirus reactivation. However, there have been no studies of CMV-specific TRM cells. Using the natural mouse herpesvirus, murine (M)CMV, our data show that many MCMV-specific TRM cells developed in the salivary and mammary glands - two sites from which HCMV and MCMV are known to be shed. More broadly, the salivary and mammary glands are two sites from which several human herpesviruses are shed. The ontogeny and function of TRM cells is poorly defined, and this gap is critical because these T cells are best positioned and possibly critical for controlling herpesvirus reactivation. Moreover, the promotion of such "first responders" - cells positioned at the site of pathogen invasion - is the major advantage of CMV- vectored vaccines. Aim 1: We will determine whether MCMV-specific TRM cells control viral latency and whether vaccines that elicit TRM formation will limit viral replication. Aim 2: Both repeated antigen recognition and the local cytokine environment are thought to modulate TRM development. Critically, infection with a spread-defective ¿gL-MCMV, which can not spread to the salivary gland, increased the formation of salivary gland MCMV-specific TRM cells, implying that viral replication or repeated antigen recognition by T cells antagonizes TRM development. We will distinguish between these possibilities using a series of recombinant viruses. Aim 3: Our preliminary data show that memory inflation in circulation is driven by a competition for viral antigen. T cells that successfully compete, inflate; those that fail to compete do not. Remarkably, our data suggest that MCMV-specific TRM cells were enriched for T cells that do not undergo memory inflation. Thus, we will determine whether T cells that fail to compete for MCMV antigen are preferentially enriched in the TRM pool. Together, these experiments will determine the ontogeny and function of MCMV-specific TRM cells that reside at these critical mucosal sites of herpesvirus shedding.

摘要：巨细胞病毒（CMV）是一种普遍存在的疱疹病毒，可建立系统性的，持续的感染。 CMV很少引起人类严重疾病 检查病毒。实际上，CMV刺激了人类循环中最大的已知T细胞群体。这些 T细胞在称为“记忆膨胀”的过程中随着时间的推移积聚，并通过关闭病毒来控制CMV 潜伏期重新激活。由于这些原因，CMV可以作为针对此类疾病的新疫苗的工具 作为癌症和艾滋病毒。但是，当病毒是 传输给孕妇。那就是预防CMV传输的疫苗被评为最高优先级 由医学研究所。了解病毒脱落部位的免疫外护理将是 防止传播和CMV疾病。最近的工作表明，T细胞种群称为“居民 记忆“ T细胞（TRM）是在可能面临病毒重新激活的体内部位建立的。的确，TRM细胞 可能有助于控制疱疹病毒重新激活。但是，尚无对CMV特异性TRM细胞的研究。 使用天然小鼠疱疹病毒，鼠（M）CMV，我们的数据表明许多MCMV特异性TRM细胞 在唾液腺和乳腺中开发 - 已知HCMV和MCMV的两个地点 棚。更广泛地说，唾液和乳腺是两个人类疱疹病毒的两个位置 脱落。 TRM细胞的个体发育和功能的定义很差，并且该差距至关重要，因为这些t 细胞最适合定位，对于控制疱疹病毒重新激活可能至关重要。而且，晋升 在病原体入侵部位位于病原体部位的这种“第一反应者” - 是CMV-的主要优势 矢量疫苗。目标1：我们将确定MCMV特异性TRM细胞是否控制病毒潜伏期和 引起TRM形成的疫苗是否会限制病毒复制。目标2：均重复抗原识别 局部细胞因子环境被认为可以调节TRM的开发。至关重要的是感染 无法扩散到唾液腺的扩散缺陷»GL-MCMV增加了唾液的形成 腺体MCMV特异性TRM细胞，这意味着T细胞的病毒复制或重复抗原识别 对抗TRM的发展。我们将使用一系列重组来区分这些可能性 病毒。目标3：我们的初步数据表明，流通中的记忆通胀是由病毒竞争驱动的 抗原。成功竞争，充气的T细胞；那些未能竞争的人没有。值得注意的是，我们的数据 表明MCMV特异性的TRM细胞富含不经历记忆膨胀的T细胞。那，我们 将确定未能争夺MCMV抗原的T细胞优选富含TRM池。 总之，这些实验将确定驻留的MCMV特异性TRM细胞的个体发育和功能 在这些关键的疱疹病毒脱落的粘膜部位。