Selection of inflationary and tissue-resident T cells during MCMV infection

描述（由申请方提供）：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，因为系统的，终身的免疫监视可以控制病毒。事实上，CMV刺激人类循环中最大的已知T细胞群。这些T细胞在一个称为“记忆膨胀”的过程中随着时间的推移而积累，并通过关闭潜伏期的病毒再激活来全身迁移以控制CMV。由于这些原因，CMV可以作为一种工具，用于对抗癌症和HIV等疾病的新疫苗。然而，关于CMV如何在免疫监视中成功地重新激活以周期性地从宿主脱落，还有很多未知之处。当病毒传播给孕妇时，CMV可以在发育中的胎儿中引起毁灭性的疾病。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，一种称为“常驻记忆”T细胞（TRM）的T细胞群在体内可能面临病毒再激活的部位建立。事实上，TRM细胞可能有助于控制疱疹病毒的再激活。然而，还没有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发育-已知MCMV从这两个部位脱落。TRM细胞的个体发育定义不明确，这种差距是至关重要的，因为这些T细胞是最好的位置，可能是控制疱疹病毒再活化的关键。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。当前提案的目标1将表征MCMV特异性TRM细胞，确定它们是否定位于感染的上皮，以及它们的维持是否依赖于已知的参与者-即TGF-β，CD 103（β E 7整联蛋白）和CD 69。目的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在唾液腺中复制时间延长，并且在唾液腺中容易再活化，这是疱疹病毒在脱落部位的典型特征。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细胞是否因为局部MCMV感染而发展，或者尽管如此。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T细胞则不会。值得注意的是，我们的数据表明MCMV特异性TRM细胞富集了不经历记忆膨胀的T细胞。因此，目的3将确定未能竞争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驻留T细胞池。

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.