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的发展是因为系统性的，终身的免疫监视可控制病毒，因此很少在人类中引起严重的疾病。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而系统地迁移以控制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，对于CMV如何成功重新激活以在免疫监视的中期从宿主定期脱落，这仍然是未知的。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外科手术将是防止传播和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细胞在唾液腺和乳腺中开发了 - 已知MCMV被脱落的两个地点。 TRM细胞的个体发育的定义很差，并且该差距至关重要，因为这些T细胞最适合控制疱疹病毒重新激活，可能是至关重要的。此外，促进这种“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。当前建议的目标1将表征MCMV特异性的TRM细胞，确定它们是否本地化为受感染的上皮，以及它们的维护是否取决于已知参与者 - 即TGF-®，CD103（CD103（EQUL）（EQUE 7 Integin）和CD69。 AIM 2将确定MCMV特异性TRM细胞的发展是否取决于局部病毒复制或MCMV免疫进化的有效性。 MCMV在唾液腺中经历了长时间的复制，并在那里很容易重新激活，这是脱落部位的疱疹病毒的典型代表。但是，MCMV免疫进化被认为在唾液腺中非常有效。这是，我们将确定MCMV特异性TRM细胞是由于局部MCMV感染而开发的，还是出现了。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，充气的T细胞；那些未能竞争的人没有。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。 AIM 3将确定未能争夺MCMV抗原的T细胞更有可能富集在TRM池中，以及T细胞受体对病毒肽的亲和力是否决定加入通货膨胀或居民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