Vaccination to generate protective tissue resident T cells

描述(申请人提供)：适应性免疫记忆，防止微生物感染，传统上被认为是由血液中循环的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中动员到外周上皮组织来对抗感染，但一旦感染得到解决，它们就会回到血液和淋巴结中。这款变革性的R01应用程序挑战了这一主流模式。最近，我们和其他人证明了在人类和小鼠的外周组织中都可以发现大量的记忆T细胞，其中大部分是在皮肤中完成的。在正常情况下，正常人皮肤中的T细胞是血液中T细胞的两倍。皮肤归巢记忆T细胞在正常皮肤中的含量是血液中的20倍。这些皮肤驻留记忆T细胞(TRM)具有不同的T细胞受体，可以很容易地通过TCR或细胞因子激活，具有多功能，并具有巨大的增殖潜力。因此，TRM不仅仅是位于意想不到位置的记忆T细胞。相反，它们是一个独特的、不完全具有特征的群体，具有许多功能和表型特征，这些特征将它们与血液中循环的记忆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存在类似的TRM种群。在小鼠模型中，越来越多的证据表明，T细胞在病原体攻击后被招募到皮肤和其他上皮组织，然后可以作为TRM长期存在。至少有两项针对皮肤病毒感染的独立研究表明，这些TRM，而不是从血液中获取的抗体或中药，提供了对抗病毒挑战的主要保护，即使在最初感染缓解许多个月后也是如此。在肺部、胃肠道甚至中枢神经系统感染后，也发现了类似的T细胞群。这些TRM主要由最初在引流组织的淋巴结中被激活的T细胞(如NAOVE T细胞)组成，因此代表了组织选择性病原体特有的组织特异性T细胞的常驻舰队。因此，我们提出了一个范式转换假说：保护性免疫记忆主要是由随着时间推移在上皮组织中积累的TRM介导的。我们建议，针对病原体的疫苗接种策略应该特别设计，以促进这些外周上皮TRM的产生。 公共卫生相关性：防止微生物感染的获得性免疫记忆传统上被认为是由血液中循环的T细胞和次级淋巴组织介导的。因此，我们提出了一个范式转换假说：人类的保护性免疫记忆主要是由先前未被认识和特征的驻留在上皮组织(TRM)上的独特记忆T细胞群介导的，这些T细胞在宿主的生命周期中积累。因此，应专门设计针对病原体的疫苗接种策略，以促进这些保护性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.