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：
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
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/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

项目摘要

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，可引起全身性持续感染。 CMV 很少在人类中引起严重疾病，因为全身性、终生的免疫监视可以保持事实上，CMV 会刺激人类循环中已知最大的 T 细胞群。 T 细胞在称为“记忆膨胀”的过程中随着时间的推移而积累，并通过关闭病毒来控制 CMV 由于这些原因，CMV 可以作为针对诸如此类疾病的新疫苗的工具。然而，当病毒感染时，CMV 可能会对发育中的胎儿造成毁灭性的疾病。因此，预防巨细胞病毒传播的疫苗被认为是最优先考虑的事情。了解病毒脱落部位的免疫监测将是实现这一目标的关键。预防传播和 CMV 疾病最近的研究表明，一种称为“常驻细胞”的 T 细胞群。记忆”T 细胞 (TRM) 建立在体内可能面临病毒重新激活的部位。事实上，TRM 细胞可能有助于控制疱疹病毒的重新激活，但目前还没有针对 CMV 特异性 TRM 细胞的研究。使用天然小鼠疱疹病毒，小鼠 (M)CMV，我们的数据显示许多 MCMV 特异性 TRM 细胞在唾液腺和乳腺中发育，这两个部位是 HCMV 和 MCMV 已知的产生地更广泛地说，唾液腺和乳腺是多种人类疱疹病毒的传播场所。 TRM 细胞的个体发育和功能尚不明确，而这一差距至关重要，因为这些 TRM 细胞。细胞处于最佳位置，并且对于控制疱疹病毒重新激活可能至关重要。这种“第一反应者”——位于病原体入侵部位的细胞——是 CMV 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和引发 TRM 形成的疫苗是否会限制病毒复制目标 2：两者均重复抗原识别。关键的是，局部细胞因子环境被认为可以调节 TRM 的感染。扩散缺陷 ¿ gL-MCMV不能扩散到唾液腺，但增加了唾液腺的形成腺体 MCMV 特异性 TRM 细胞，意味着病毒复制或 T 细胞重复抗原识别我们将使用一系列重组来区分这些可能性。目标 3：我们的初步数据表明，循环中的内存膨胀是由病毒竞争驱动的。值得注意的是，成功竞争的 T 细胞会膨胀；而那些未能竞争的 T 细胞则不会。表明 MCMV 特异性 TRM 细胞富含不经历记忆膨胀的 T 细胞。将确定未能竞争 MCMV 抗原的 T 细胞是否优先富集在 TRM 池中。这些实验将共同确定 MCMV 特异性 TRM 细胞的个体发育和功能。在疱疹病毒脱落的这些关键粘膜部位。