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

基本信息

批准号：
8986152
负责人：
Christopher M Snyder
金额：
$ 38.75万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
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/8986152
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 Health 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 Replication Virus Shedding Work cytokine emergency service responder mucosal site novel novel vaccines pathogen pressure prevent pup reactivation from latency recombinant virus research study therapy design tool transmission process

项目摘要

DESCRIPTION (provided by applicant): 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 cannot 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 fil 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.

描述（由适用提供）：巨细胞病毒（CMV）是一种无处不在的疱疹病毒，它建立了系统性的，持续的感染。 CMV很少引起人类严重疾病，因为系统性的，终身的免疫监视可以控制病毒。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累，并通过从潜伏期中关闭病毒重新激活来控制CMV。由于这些原因，CMV可以作为针对癌症和艾滋病毒等疾病的新疫苗的工具。但是，当病毒传播给孕妇时，CMV会在发育中的胎儿中引起毁灭性疾病。这是医学研究所将防止CMV传播的疫苗评为最高优先级。了解病毒脱落部位的免疫监测将是防止传播和CMV疾病的关键。最近的工作表明，在可能面临病毒重新激活的体内部位建立了称为“居民记忆” T细胞（TRM）的T细胞群体。实际上，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细胞在唾液和乳腺网格中开发 - 已知HCMV和MCMV的两个地点是脱落的。更广泛地说，唾液腺和乳腺是两个人类疱疹病毒的两个部位。 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细胞最适合于控制疱疹病毒重新激活。此外，促进这种“第一反应者” - 位于病原体侵袭部位的细胞 - 是CMV-毒性疫苗的主要优势。目标1：我们将确定MCMV特异性TRM细胞是否控制病毒潜伏期以及引起TRM形成的疫苗是否会限制病毒复制。 AIM 2：重复抗原识别和局部细胞因子环境都被认为可以调节TRM发育。至关重要的是，无法扩散到唾液腺的扩散缺陷�GL-MCMV的感染增加了唾液腺MCMV特异性TRM细胞的形成，这意味着该病毒复制或通过T细胞重复抗原识别TRM发育。我们将使用一系列重组病毒区分这些可能性。 AIM 3：我们的初步数据表明，循环中的记忆膨胀是由病毒抗原的竞争驱动的。成功竞争，充气的T细胞；那些要竞争的人没有。值得注意的是，我们的数据表明，MCMV特异性TRM细胞富含不经历记忆膨胀的T细胞。那我们将确定失败的T细胞是否为了争夺MCMV的竞争，最好将抗原富含在TRM池中。总之，这些实验将确定位于疱疹病毒脱落的这些关键粘膜位点的MCMV特异性TRM细胞的个体发育和功能。