Vaccination to generate protective tissue resident T cells

描述（由申请人提供）：适应性免疫记忆保护机体免受微生物感染，传统上认为是由血液循环中的T细胞和次级淋巴组织介导的。根据这一观点，虽然记忆T细胞可以很容易地从血液动员到外周上皮组织来对抗感染，但一旦感染解决，它们会返回血液和淋巴结。这个变革性的R01应用程序挑战了这个流行的范例。最近，我们和其他人已经证明，记忆T细胞可以在人类和小鼠的外周组织中大量存在，其中大部分工作是在皮肤中完成的。正常情况下，人体皮肤中的T细胞数量是血液中的两倍。皮肤归巢记忆T细胞在正常皮肤中的数量是血液中的20倍。这些皮肤常驻记忆细胞（TRM）具有多种T细胞受体库，可以很容易地通过TCR或细胞因子激活，是多功能的，具有很大的增殖潜力。因此，TRM不是简单的记忆T细胞在一个意想不到的位置。相反，它们是一种独特的、不完全特征化的群体，具有许多功能和表型特征，将它们与血液循环中的记忆T细胞区分开来。越来越多的证据表明，在肺和胃肠道以及生殖粘膜中也存在类似的TRM群体。在小鼠模型中有越来越多的证据表明，在病原体攻击后，T细胞被招募到皮肤和其他上皮组织，然后可以作为TRM长期存在。至少有两项独立的皮肤病毒感染研究表明，这些TRM，而不是从血液中募集的抗体或中药，即使在最初感染解决几个月后，也能提供抵抗病毒攻击的主要保护。在肺部、胃肠道甚至中枢系统感染后也发现了相似的T细胞群。这些TRM主要由T细胞组成，这些T细胞最初（作为初始T细胞）在引流组织的淋巴结中被激活，因此代表了组织特异性T细胞的常驻舰队，对组织选择性病原体具有特异性。因此，我们提出了一个范式转换的假设：保护性免疫记忆主要是由上皮组织中积累的TRM介导的。我们建议针对病原体的疫苗接种策略应专门设计以增强这些外周上皮TRM的产生

DESCRIPTION (provided by applicant): Adaptive immune memory that protects against microbial infection is traditionally thought to be mediated by T cells circulating in blood and through secondary lymphoid tissues. According to this view, while memory T cells can be readily mobilized from blood to peripheral epithelial tissues to fight infection, they would return to blood and lymph nodes once the infection was resolved. This transformative R01 application challenges this prevailing paradigm. Very recently, we and others have demonstrated memory T cells can be found in abundance in the peripheral tissues of both humans and mice, with the majority of this work being done in skin. Under normal conditions, twice as many T cells reside in normal human skin as in blood. Skin- homing memory T cells are 20-fold more abundant in normal skin than in blood. These skin resident memoryT cells (TRM) have a diverse T cell receptor repertoire, can be readily activated through the TCR or by cytokines, are polyfunctional, and have great proliferative potential. Therefore, TRM are not simply memory T cells in an unexpected location. Rather, they are a unique and incompletely characterized population, having many functional and phenotypic qualities that differentiate them from memory T cells that circulate in blood. Evidence is accumulating that similar populations of TRM exist in lung and GI tract, as well as reproductive mucosa. There is a growing body of evidence in murine models suggesting that T cells are recruited to skin and other epithelial tissues after pathogen challenge, and then can persist there long term as TRM. At least two separate studies examining viral infection of skin have demonstrated that these TRM, rather than antibody or TCM recruited from blood, provide principal protection against viral challenge, even many months after resolution of the initial infection. Similar populations of T cells are being identified after infection in lung, GI tract, and even CNS. These TRM consist largely of T cells that were originally (as naove T cells) activated in lymph nodes draining that tissue, and thus represent a resident armada of tissue specific T cells specific for tissue selective pathogens. We thus propose a paradigm-shifting hypothesis: that protective immune memory is mediated largely by TRM that have accumulated over time in epithelial tissues. We propose that vaccination strategies against pathogens should be designed specifically to enhance the generation of these peripheral epithelial TRM PUBLIC HEALTH RELEVANCE: Adaptive immune memory that protects against microbial infection is traditionally thought to be mediated by T cells circulating in blood and through secondary lymphoid tissues. We thus propose a paradigm-shifting hypothesis: that protective immune memory in humans is mediated principally by previously unappreciated and uncharacterized populations of unique memory T cells resident to epithelial tissues (TRM) that have accumulated over the life of the host. Vaccination strategies against pathogens should thus be designed specifically to enhance the generation of these protective TRM.