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很少在人类中引起严重疾病，因为系统性的、终身的免疫监视使病毒受到控制。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，并通过关闭潜伏期的病毒再激活来控制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，当病毒传播给孕妇时，CMV可在发育中的胎儿中引起毁灭性疾病。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HCMV和MCMV从这两个部位脱落。更广泛地说，唾液腺和乳腺是几种人类疱疹病毒脱落的两个部位。TRM细胞的个体发育和功能定义不清，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”--位于病原体入侵位点的细胞--是CMV载体疫苗的主要优点。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。目的2：反复的抗原识别和局部细胞因子环境被认为调节TRM的发展。重要的是，感染不能扩散到唾液腺的扩散缺陷型μ gL-MCMV，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细胞的重复抗原识别拮抗TRM的发展。我们将使用一系列重组病毒来区分这些可能性。目的3：我们的初步数据表明，循环中的记忆膨胀是由对病毒抗原的竞争驱动的。成功竞争的T细胞会膨胀，而那些为了竞争而膨胀的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，我们将确定是否T细胞， 竞争MCMV抗原的细胞优先富集在TRM库中。总之，这些实验将确定MCMV特异性TRM细胞的个体发育和功能，这些细胞位于疱疹病毒脱落的这些关键粘膜部位。

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.