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（由申请人提供）：巨细胞病毒（CMV）是一种普遍存在的疱疹病毒，它很少会引起人类的严重疾病，因为全身性的、终生的免疫监视可以控制病毒。事实上，CMV 会刺激病毒。人类循环中已知最大的 T 细胞群随着时间的推移在称为“记忆膨胀”的过程中积累，并通过关闭潜伏期的病毒重新激活来控制巨细胞病毒。 CMV 可以作为对抗癌症和 HIV 等疾病的新疫苗的工具，但是，当病毒传播给孕妇时，CMV 可能会导致发育中的胎儿罹患毁灭性疾病。因此，预防 CMV 传播的疫苗被认为是一种有效的疫苗。医学研究所的首要任务是了解病毒脱落部位的免疫监视，这将是预防传播和 CMV 疾病的关键。最近的研究表明，在病毒脱落部位建立了一种称为“常驻记忆”T 细胞 (TRM) 的 T 细胞群。可能面临病毒的身体事实上，TRM 细胞可能有助于控制疱疹病毒的重新激活，但是，目前还没有使用天然小鼠疱疹病毒、鼠 (M)CMV 进行的研究，我们的数据表明，许多 MCMV 特异性 TRM 细胞在体内发育。唾液腺和乳腺——已知 HCMV 和 MCMV 的两个排出部位更广泛地说，唾液腺和乳腺是多种人类疱疹病毒的两个排出部位。 TRM 细胞的个体发育和功能尚不明确，并且这种间隙至关重要，因为这些 T 细胞处于最佳位置，并且可能对于控制疱疹病毒重新激活至关重要。此外，促进此类“第一反应者”（位于脱落部位的细胞）。病原体入侵 - 是 CMV 载体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发 TRM 形成的疫苗是否会限制病毒复制。细胞因子环境被认为可以调节 TRM 的发展，重要的是，传播缺陷型感染 ¿ gL-MCMV 不能扩散到唾液腺，但增加了唾液腺 MCMV 特异性 TRM 细胞的形成，这意味着病毒复制或 T 细胞重复的抗原识别会拮抗 TRM 的发育，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，循环中的记忆膨胀是由病毒抗原的竞争驱动的，而那些成功竞争的 T 细胞则不会。 MCMV 特异性 TRM 细胞富集了不经历记忆膨胀的 T 细胞，因此，我们将确定 T 细胞是否会失败。这些实验将共同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。