Mucosal T Cell Memory to Pathogens

 描述(申请人提供)：大多数再感染是在构成与外部世界的一线屏障的组织内开始的，例如胃肠道、呼吸道和 泌尿生殖道粘膜。记忆性CD8T细胞通过扫描宿主细胞表面来保护细胞内的病原体，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，CD8记忆T细胞的一个主要谱系，称为驻留记忆(TRM)，占据粘膜组织而不再循环。然而，TRM是对屏障组织中启动的再感染事件的第一反应者，它们极大地加速了病原体控制，减少了疾病。因此，诱导TRM可能是针对粘膜病原体的T细胞疫苗的一个重要目标。由于TRM不存在于容易采集的外周血中，也因为它们以前被与循环的效应记忆T细胞混为一谈，TRM还没有得到很好的表征。这项建议将解决我们目前对TRM的理解中的主要差距。TRM包括不同的子集，但共有的谱系定义标记的假设将通过小鼠模型感染、副生物手术和转录图谱进行测试。定义和验证真正的标记将使研究人员能够检查TRM生物学，即使在监测再循环是不切实际的或不可能的系统中(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细胞记忆将支持对TRM寿命、维护要求和非淋巴组织中的动态平衡调节问题的研究；这些问题与疫苗接种直接相关。虽然CD8 T细胞被认为是免疫系统中与抗体完全分开的一个分支，但具有挑衅性的初步数据支持这样一种假设，即CD8+TRM在粘膜内充当感觉细胞，能够在再次感染时迅速增加粘膜抗体浓度。这项建议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相结合以预防艾滋病毒等难治病原体提供进一步的理论基础。最后，这项建议将测试新的假设与扩大TRM建立在所需的粘膜部位使用一种策略，可以可行地翻译到人类。实际实现这一目标仍然是T细胞的主要雄心之一 疫苗学。总而言之，将利用重要的专业知识将基础生物学研究到T驻留记忆这一新兴领域，具有非常高的健康相关性和潜在的影响。在TRM调节、定义标志物、寿命、功能和对操作的允许性方面的新发现可能不仅对疫苗，而且对组织中其他T细胞介导的免疫过程产生广泛的影响，包括免疫病理学、肿瘤免疫监视和自身免疫。

 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.