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: 8690204
• 负责人: Christopher M Snyder
• 金额: $ 36.43万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-08 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690204
• 关键词: Acyclovir; Adoptive Transfer; Affinity; Antigens; Blood Circulation; Cells; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Disease; Economic Inflation; Epithelium; Equilibrium; Face; Fetus; Genes; Growth; HIV; Herpesviridae; Herpesviridae Infections; Histologic; Human; Immune; Immunodominant Antigens; Immunologic Surveillance; Infection; Institute of Medicine (U.S.); Integrins; Knowledge; Life; MHC Class I Genes; Maintenance; Malignant Neoplasms; Mammary gland; Memory; Modeling; Mus; OVA-8; Ovalbumin; Peptides; Play; Population; Positioning Attribute; Pregnant Women; Process; Residencies; Retroviridae; Role; Salivary Glands; Site; 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 Diseases; Virus Shedding; Work; congenic; emergency service responder; mucosal site; novel; novel vaccines; pathogen; prevent; reactivation from latency; research study; therapy design; tool; transmission process

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) is a ubiquitous herpesvirus that establishes a systemic, persistent infection. CMV has evolved to rarely cause 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 migrate systemically to 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, much remains unknown about how CMV manages to successfully reactivate to be periodically shed from a host, in the midst of immune surveillance. 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-specifics TRM cells developed in the salivary and mammary glands - two sites from which MCMV is known to be shed. The ontogeny 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 of the current proposal will characterize MCMV-specific TRM cells, determine whether they localize to infected epithelium, and whether their maintenance depends on known players - namely TGF-¿, CD103 (¿E¿7 integrin) and CD69. Aim 2 will determine whether the development of MCMV-specific TRM cells depends on local viral replication or the efficacy of MCMV immune evasion. MCMV undergoes prolonged replication in the salivary gland and is readily reactivated there, which is typical of herpesviruses at sites of shedding. However, MCMV immune evasion is thought to be highly effective in the salivary gland. Thus, we will determine whether MCMV-specific TRM cells develop because of the local MCMV infection or in spite of it. Finally, 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, Aim 3, will determine whether T cells that fail to compete for MCMV antigen are preferentially enriched in the TRM pool and whether the affinity of the T cell receptor for viral peptide dictates the decision to join the inflationary or resident T cell pools.

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。 CMV 已经进化到很少在人类中引起严重疾病，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 细胞随着时间的推移，在一个称为“记忆膨胀”的过程中积累，并系统性地迁移，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，在免疫监视过程中，巨细胞病毒如何成功地重新激活并定期从宿主体内排出，目前仍不清楚。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，我们的数据表明，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 MCMV 脱落的部位。 TRM 细胞的个体发育尚不明确，这种差距至关重要，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。当前提案的目标 1 将描述 MCMV 特异性 TRM 细胞的特征，确定它们是否定位于受感染的上皮，以及它们的维持是否依赖于已知的参与者 - 即 TGF-¿、CD103（¡E¿7 整合素）和 CD69。目标 2 将确定 MCMV 特异性 TRM 细胞的发育是否取决于局部病毒复制或 MCMV 免疫逃避的功效。 MCMV 在唾液腺中经历长时间的复制，并且很容易在那里重新激活，这是典型的疱疹病毒在脱落部位的情况。然而，MCMV 免疫逃避被认为在唾液腺中非常有效。因此，我们将确定 MCMV 特异性 TRM 细胞的发育是由于局部 MCMV 感染还是尽管如此。最后，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。成功竞争的 T 细胞会膨胀；那些未能竞争的人则没有。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，目标 3 将确定无法竞争 MCMV 抗原的 T 细胞是否优先富集在 TRM 池中，以及 T 细胞受体对病毒肽的亲和力是否决定加入膨胀或常驻 T 细胞池的决定。

项目成果

Hematopoietic cell-mediated dissemination of murine cytomegalovirus is regulated by NK cells and immune evasion.

• DOI: 10.1371/journal.ppat.1009255
• 发表时间: 2021-01
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Zhang S;Springer LE;Rao HZ;Espinosa Trethewy RG;Bishop LM;Hancock MH;Grey F;Snyder CM
• 通讯作者: Snyder CM