Skin Homing T Cells

皮肤归巢 T 细胞

• 批准号: 8827484
• 负责人: THOMAS S. KUPPER
• 金额: $ 4.41万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-28 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827484
• 关键词: Adoptive Transfer; Anatomy; Antigens; Applications Grants; Asthma; Autoimmune Diseases; Biology; Blocking Antibodies; Blood; Breeding; Candida albicans; Cell Lineage; Cells; Contact hypersensitivity; Coupled; Data; Dermal; Diagnosis; Dinitrochlorobenzene; Dinitrofluorobenzene; Disease; Distant; Dose; Ear; Effector Cell; Environment; Epithelial; Epitopes; Eragrostis; Figs - dietary; Funding; Generations; Genetic Engineering; Genetically Engineered Mouse; Goals; Grant; Health; Homing; Host Defense; Hour; Human; Image; Immune; Immune response; Immunity; Infection; Infectious Skin Diseases; Infiltration; Joints; Life; Location; Lung; Maintenance; Measures; Mediating; Memory; Modeling; Mus; Organ; Pathogenesis; Peripheral; Phase; Phenotype; Play; Population; Psoriasis; Regulatory T-Lymphocyte; Relative (related person); Research Personnel; Role; Signal Transduction; Skin; Specificity; Stratum corneum; Swelling; Synapses; T Virus; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Time; Tissues; Vaccinia virus; Viral; Virus Diseases; Work; antigen challenge; base; deep sequencing; experience; extracellular; human data; human disease; human tissue; in vivo; innovation; long term memory; lymph nodes; man; mouse model; new technology; novel; pathogen; programs; research study; response; trafficking

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.

描述（由申请人提供）：在皮肤和其他上皮组织中发现T驻留记忆（TRM）细胞，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的发现和病毒感染小鼠模型中皮肤TRM的初步表征做出了贡献，但这些重要的细胞仍然知之甚少。我们确实知道，皮肤中的TRM提供了更迅速和更有效的保护，防止致病性病毒的再次感染，而且TRM往往不会从皮肤再循环到血液中。VACV皮肤感染导致抗原特异性TRM的播种对受感染皮肤最有效，对远端皮肤的效果略差，对与环境接触的其他上皮器官的效果较差（但仍然显著）。、肺)。总之，我们的小鼠和人类数据促使我们做出两个相关的假设：首先，这些TRM是一般保护性免疫记忆方面最重要的T细胞，其次，它们在人体中的功能失调激活是大多数T细胞介导的外周组织疾病的基础，包括皮肤（牛皮癣）、肺（哮喘）、肠道（IBD）、关节（RA）和中枢神经系统（MS）。如果这些假设是正确的，那么更好地了解这些TRM的基本生物学对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。利用T细胞受体深度测序，我们意外发现组织中的每个TRM在淋巴结TCM室中都有一个克隆对应体，强烈认为TRM和TCM来自共同的初始T细胞前体。因此，不是抗原特异性本身，而是它们的解剖位置使TRM在快速保护性免疫方面优于中药。TRM和TCM之间的相互作用，以及在随后的抗原挑战中招募现有TCM成为新的TRM也是该资助的重点。为了扩大我们的优势，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，结合基因工程小鼠、新型成像方法和TCR深度测序，试图更好地了解TRM是如何产生和维持的，以及它们在病毒、细胞外病原体和环境抗原驱动疾病中维持免疫记忆的作用。这项资助对人类疾病非常重要，使用创新方法，以新技术为基础，提出了雄心勃勃但可行的方法，由经验丰富的研究人员在一个支持性的环境中实施，并热切希望能得到资助。