Skin Homing T Cells

描述（由申请人提供）：皮肤和其他上皮组织中T驻留记忆（TRM）细胞的发现彻底改变了我们对保护性T细胞记忆的理解。虽然我们很高兴我们长期的R01资助为人类TRM的发现做出了贡献，并且在病毒感染的小鼠模型中初步表征了皮肤TRM，但这些重要细胞仍然知之甚少。我们确实知道，皮肤中的TRM提供了更快速和有效的保护，防止病原性病毒的再次感染，并且TRM往往不会从皮肤重新循环到血液中。VACV皮肤感染导致抗原特异性TRM最有效地接种到感染的皮肤，稍微不那么有效地接种到远处皮肤，并且不那么有效地（但仍然显著地）接种到与环境交界的其他上皮器官（例如，肺）。综上所述，我们的鼠和人数据促使我们做出两个相关的假设：第一，这些TRM是关于一般保护性免疫记忆的最重要的T细胞，第二，它们在人体中的功能障碍性激活是大多数T细胞介导的外周组织疾病的基础，包括皮肤（银屑病）、肺（哮喘）、肠道（IBD）、关节（RA）和CNS（MS）。如果这些假设是正确的，那么更好地理解这些TRM的基础生物学对于我们理解如何诊断和更有效地治疗广泛的人类疾病以及配置增强对病原体的保护性免疫的方法至关重要。使用T细胞受体深度测序，我们已经做出了意想不到的观察，即组织中的每个TRM在淋巴结TCM隔室中具有克隆对应物，强烈认为TRM和TCM来自共同的幼稚T细胞前体。因此，这不是抗原特异性本身，而是它们的解剖位置，使TRM上级中医药在快速保护性免疫方面。TRM和TCM之间的相互作用，以及在随后的抗原攻击后招募现有TCM成为新的TRM也是这项补助金的重点。为了扩大我们Vantage，我们将使用三种不同的皮肤免疫反应模型：接触性超敏反应（CHS）、牛痘病毒（VACV）感染和白色念珠菌感染，加上基因工程小鼠、新的成像方法和TCR的深度测序，试图更好地了解TRM是如何产生和维持的，以及它们在维持病毒免疫记忆中发挥什么作用，细胞外病原体和环境抗原驱动的疾病。该基金对人类疾病具有重要意义，采用创新方法并基于新技术，提出了雄心勃勃但可行的方法，由经验丰富的研究人员在支持性环境中进行，并热切希望能够获得资助。

DESCRIPTION (provided by applicant): The discovery of T resident memory (TRM) cells in skin and other epithelial tissues has revolutionized our understanding of protective T cell memory. While we are delighted that our long standing R01 grant has contributed to the discovery TRM in humans, and the initial characterization skin TRM in mouse models of viral infection, these important cells remain poorly understood. We do know that TRM in skin provide much more rapid and potent protection against re-infection with pathogenic virus, and that TRM tend to not re-circulate from skin to blood. VACV skin infection results in the seeding of antigen specific TRM most effectively to infected skin, slightly less effectively to distant skin, and leas effectively (but still significantly) to other epithelial organs that interface the environment (e.., lung). Taken together, our murine and human data provoke us to make two related hypotheses: first, that these TRM are the most important T cells with regard to protective immune memory in general, and second, that their dysfunctional activation in man underlies most T cell mediated diseases of peripheral tissues, including skin (psoriasis), lung (asthma), gut (IBD), joint (RA), and CNS (MS). If these hypotheses are correct, then a better understanding of the fundamental biology of these TRM is central to our understanding of how to diagnose and more effectively treat a broad spectrum of human diseases, as well as to configure means to enhance protective immunity against pathogens. Using T cell receptor deep sequencing, we have made the unexpected observation that every TRM in tissue has a clonal counterpart in the lymph node TCM compartment, strongly arguing that TRM and TCM arise from a common naive T cell precursor. Thus, it is not antigen specificity per se, but rather their anatomic location that make TRM superior to TCM in terms of rapid protective immunity. The interplay between TRM and TCM, and the recruitment of existing TCM to become new TRM upon subsequent antigen challenge is also a focus of this grant. To broader our vantage point, we will use three distinct models of skin immune responses: contact hypersensitivity (CHS), vaccinia virus (VACV) infection, and C.albicans infection, coupled with genetically engineered mice, novel imaging approaches, and deep sequencing of the TCR, to try to better understand how TRM are generated and maintained, and what role they play in the maintenance of immune memory in viral, extracellular pathogen, and environmental antigen driven diseases. This grant is highly significant to human disease, uses innovative approaches and is based on novel technology, proposes ambitious but feasible approaches to be performed by experienced investigators in a supportive environment, and fervently hope it can be funded.