Mucosal T Cell Memory to Pathogens

 描述（由申请人提供）：大多数再感染是在构成与外界的前线屏障的组织内开始的，如胃肠道、呼吸道和 泌尿生殖道粘膜记忆性CD8 T细胞通过扫描宿主细胞表面来保护细胞内病原体，因此它们的迁移模式直接影响它们检测再感染的能力。最近发现，记忆性CD8 T细胞的主要谱系，称为驻留记忆（TRM），占据粘膜组织而不再循环。然而，TRM作为第一反应者对抗在屏障组织中引发的再感染事件，并且它们大大加速病原体控制并减少疾病。因此，引发TRM可能是针对粘膜病原体的T细胞疫苗的重要目标。因为TRM不存在于容易取样的外周血中，并且还因为它们先前与再循环效应记忆T细胞混淆，所以TRM尚未被很好地表征。该提案将解决我们目前对TRM的理解中的主要差距。TRM包含不同子集，但共享谱系定义标志物的假设将使用小鼠中的模型感染、联体手术和转录谱进行测试。定义和验证真正的标记将允许其他研究人员检查TRM生物学，即使在监测再循环不切实际或不可能的系统中（例如在人类中），并将使该领域建立在更坚实的分子基础上。初步数据表明，TRM调节不同于传统的T细胞记忆将支持调查TRM的寿命，维护要求，以及在非淋巴组织的稳态调节问题，与疫苗接种的直接相关的问题。虽然CD8 T细胞被认为是免疫系统中与抗体完全独立的一个分支，但引发争议的初步数据支持这样的假设，即CD8+ TRM在粘膜内充当感觉细胞，能够在再感染的情况下快速增加粘膜抗体浓度。该提案将探索这一新观察的潜在机制，这可能为将T细胞疫苗接种方法与传统体液疫苗方法结合起来提供进一步的理论基础，以保护免受难治性病原体如HIV的侵害。最后，该提案将测试新的假设，增加TRM建立在所需的粘膜部位使用的策略，可以可行地翻译给人类。实际上实现这一目标仍然是T细胞免疫的主要目标之一。 疫苗学总之，重要的专业知识将被利用来追求基础生物学进入T驻留记忆的新兴领域，具有非常高的健康相关性和潜在的影响。这里关于TRM调节、定义标志物、寿命、功能和对操作的容许性的新发现不仅对疫苗，而且对组织中的其他T细胞介导的免疫过程，包括免疫病理学、肿瘤免疫监视和自身免疫，具有广泛的影响。

 DESCRIPTION (provided by applicant): Most reinfections are initiated within tissues that comprise a frontline barrier with the outside world, such as the gastrointestinal, respiratory, and genitourinary mucosae. Memory CD8 T cells protect against intracellular pathogens by scanning host cell surfaces, so their migration patterns directly impact their ability to detect reinfection. It was recently discovered that a major lineage of memory CD8 T cells, termed resident memory (TRM), occupies mucosal tissues without recirculating. However, TRM act as first responders against reinfection events that are initiated in barrier tissues, and they greatly accelerate pathogen control and decrease disease. Thus, eliciting TRM may be an important goal for T cell vaccines against mucosal pathogens. Because TRM are not present within the easily sampled peripheral blood, and also because they were previously conflated with recirculating effector memory T cells, TRM have not yet been well characterized. This proposal will address major gaps in our current understanding of TRM. The hypothesis that TRM comprise different subsets, but share lineage defining markers will be tested using model infections in mice, parabiotic surgeries, and transcriptional profiling. Defining and validating bona fide markers will allow othe investigators to examine TRM biology even in systems where monitoring recirculation is impractical, or impossible (e.g. in humans), and will put the field on a firmer molecular foundation. Preliminary data indicating that TRM regulation differs from conventional T cell memories will support investigations into TRM longevity, maintenance requirements, and issues of homeostatic regulation in nonlymphoid tissues; issues with immediate relevance for vaccination. While CD8 T cells are thought to comprise an entirely separate arm of the immune system from antibodies, provocative preliminary data supports the hypothesis that CD8+ TRM act as sensory cells within the mucosae that are capable of rapidly increasing mucosal antibody concentrations in the event of reinfection. This proposal will explore the underlying mechanisms for this novel observation, which may provide further rationale for coupling T cell vaccination approaches with conventional humoral vaccine approaches for protecting against intractable pathogens such as HIV. Lastly, this proposal will test novel hypotheses related to augmenting TRM establishment within desired mucosal sites using a strategy that could be feasibly translated to humans. Practicably achieving this goal is still one of the major ambitions in T cell vaccinology. In summary, significant expertise will be leveraged to pursue fundamental biology into the emerging field of T resident memory, with very high health relatedness and potential for impact. New discoveries made here regarding TRM regulation, defining markers, longevity, function, and permissiveness to manipulation could have wide ranging impact not only for vaccines, but other T cell mediated immunological processes in tissues, including immunopathology, tumor immunosurveillance, and autoimmunity.