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: 9198197
• 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
• 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/9198197
• 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 Evasion; Immunity; Immunodominant Antigens; Immunologic Surveillance; Infection; Institute of Medicine (U.S.); Integrins; Knowledge; Life; Maintenance; Malignant Neoplasms; Mammary gland; Measures; Memory; Modeling; Mucous Membrane; Murid herpesvirus 1; Mus; OVA-8; Oral; 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; experimental study; gammaherpesvirus; mucosal site; novel; novel vaccines; pathogen; pressure; prevent; public health relevance; pup; reactivation from latency; recombinant virus; suckling; therapy design; tool; transmission process; vector vaccine

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 ΔgL-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，可引起全身性、持续性感染。巨细胞病毒很少对人类造成严重疾病，因为系统性、终生的免疫监视可以控制病毒。事实上，CMV 可刺激人体循环中已知最大的 T 细胞群。这些 T 细胞会随着时间的推移在一个称为“记忆膨胀”的过程中积累，并通过关闭病毒潜伏期的重新激活来控制 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。然而，当巨细胞病毒传播给孕妇时，可能会对发育中的胎儿造成毁灭性的疾病。因此，预防 CMV 传播的疫苗被医学研究所列为最高优先事项。了解病毒脱落部位的免疫监视将是预防传播和 CMV 疾病的关键。最近的研究表明，在体内可能面临病毒重新激活的部位建立了一种称为“常驻记忆”T 细胞 (TRM) 的 T 细胞群。事实上，TRM 细胞可能有助于控制疱疹病毒的重新激活。然而，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，即小鼠 (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，这两个部位是已知 HCMV 和 MCMV 脱落的部位。更广泛地说，唾液腺和乳腺是多种人类疱疹病毒传播的两个部位。 TRM 细胞的个体发育和功能尚不清楚，这一差距至关重要，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”（位于病原体入侵部位的细胞）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。目标 2：重复的抗原识别和局部细胞因子环境都被认为可以调节 TRM 的发展。至关重要的是，传播缺陷型 ΔgL-MCMV（无法传播到唾液腺）的感染增加了唾液腺 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病毒来区分这些可能性。目标 3：我们的初步数据表明，循环中的内存膨胀是由病毒抗原的竞争驱动的。成功竞争的 T 细胞会膨胀；那些能够竞争的人却没有。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。因此，我们将确定未能竞争 MCMV 抗原的 T 细胞是否优先富集在 TRM 库中。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。