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T Cell Tolerance & Autoimmunity to Nuclear Antigen La

T细胞耐受性

基本信息

批准号：
8277356
负责人：
A Darise Farris
金额：
$ 28.24万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-22 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8277356
关键词：
Address Adopted Adoptive Transfer Affect Antigen Presentation Antigen-Antibody Complex Antigen-Presenting Cells Antigens Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity Automobile Driving B-Lymphocytes Biological Models CD4 Positive T Lymphocytes Cell Differentiation process Cells Chromosomal translocation Chronic Cues Dendritic Cells Development Disease Disease susceptibility Effector Cell Elements Genes Haplotypes Health Helper-Inducer T-Lymphocyte Hematopoietic Human Immune Tolerance Immune system Infection Inflammation Inflammatory Interferons Interleukin-6 Ligands Lupus Lymphoid MHC Class II Genes Mediating Modeling Mus Nuclear Antigens Nucleic Acid Binding Organ Pathway interactions Peripheral Phenotype Physiological Predisposition RNA RNA Binding Regulatory T-Lymphocyte Relative (related person)Role Self Tolerance Sjogren&apos s Syndrome Structure of germinal center of lymph node Syndrome System Systemic Lupus Erythematosus T-Cell Receptor T-Lymphocyte Toll-like receptors Transgenic Mice Transgenic Organisms cell type clinically relevant design disease phenotype human TLR7 protein in vivo lupus-like male novel overexpression peripheral tolerance systemic autoimmune disease

项目摘要

DESCRIPTION (provided by applicant): RNA-binding nuclear antigens are a major class of autoantigen targeted in systemic autoimmune diseases, including systemic lupus erythematosus (SLE) and Sjvgren's syndrome (SS). The mechanisms that normally mediate immunologic tolerance to RNA-binding nuclear antigens and the specific tolerance pathways that are breached in the setting of systemic autoimmunity are not well understood, although it is known that T helper (Th) cells are crucial for disease in murine lupus models. We have developed the first and only mouse transgenic for an RNA-binding nuclear antigen-specific TCR T cell receptor (TCR) in order to delineate specific mechanisms leading to T cell tolerance. By transferring T cells specific for the clinically relevant human La/SS- B antigen (hLa) into mice transgenic for physiologic expression of hLa and tracking their numbers, phenotype and function, we will delineate the mechanisms leading to peripheral T cell tolerance (Aim 1). Preliminary studies have shown that the mode of tolerance adopted by these T cells depends on the level of antigen presentation in the recipients and that the in vivo cues promoting Foxp3+ regulatory T cells in this system differ from those previously described. Analysis of antigen presenting cell (APC) and T cell phenotypes in mice mildly (2X) over-expressing RNA-binding Toll-like receptor 7 (TLR7) in the absence of other lupus susceptibility loci suggest that one cue could be constitutive stimulation of nucleic acid-binding TLR. This hypothesis and its mechanism will be investigated in Aim 1. Mice that over-express TLR7 2X in the absence of other lupus susceptibility loci are healthy and harbor tolerant T cells, whereas mice that over-express TLR7 >4X above normal develop severe, fatal lupus that is T cell dependent. The precise peripheral tolerance mechanisms that are abrogated in CD4+ anti-hLa specific T cells following their transfer into hLa transgenic mice that express TLR7 >4X and their subsequent differentiation into distinct Th and T effector cell phenotypes will be evaluated in Aim 2. We will also determine whether these fates associate with the loss of particular tolerance mechanisms such as deletion and Foxp3+ Treg conversion, and determine the roles of IL-6 and IL-21 in promoting pathogenic Th cell differentiation in this model. Very few studies exist that have investigated the role of in vivo DC in promoting CD4+ T cell tolerance in the steady state, and no such studies for nucleic acid- binding nuclear antigens have been described. In Aim 3, we will determine whether B cells, conventional dendritic cells (DC) or plasmacytoid DC, are essential for promoting the peripheral tolerance of CD4+ T cells specific for this representative RNA-binding nuclear antigen by following the numbers, phenotype and function of anti-hLa-specific T cells in hLa transgenic mice that have been selectively depleted of these cell types. Conversely, we will determine the relative importance of B cells and DC in promoting loss of tolerance and differentiation of anti-hLa specific T cells into pathogenic Th and T effector cell types in the setting of pathogenic (>4X) TLR7 expression. These studies will define the mechanisms of CD4+ T cell tolerance and its loss for a major class of antigen that is targeted in systemic autoimmune disease. PUBLIC HEALTH RELEVANCE Systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS) are chronic, debilitating autoimmune diseases that affect the immune system. The immune systems of humans and mice have natural mechanisms designed to maintain self-tolerance and respond to infection and inflammation. We seek to understand how these elements control CD4+ T cell fate and phenotype under both steady-state and inflammatory conditions so that we can better understand the development of autoimmune disease.

描述（由申请人提供）：rna结合核抗原是针对系统性自身免疫性疾病的主要自身抗原，包括系统性红斑狼疮（SLE）和干燥综合征（SS）。尽管已知辅助性T细胞（Th）在小鼠狼疮模型中对疾病至关重要，但通常介导对rna结合核抗原的免疫耐受的机制以及在全身性自身免疫环境中被破坏的特异性耐受途径尚不清楚。我们已经开发了第一个也是唯一的小鼠转基因rna结合核抗原特异性TCR T细胞受体（TCR），以描述导致T细胞耐受的特定机制。通过将临床相关的人La/SS- B抗原（hLa）特异性T细胞转移到hLa生理表达转基因小鼠中，并跟踪其数量、表型和功能，我们将描述导致外周T细胞耐受的机制（目的1）。初步研究表明，这些T细胞所采用的耐受模式取决于受体的抗原呈递水平，并且该系统中促进Foxp3+调节性T细胞的体内信号与先前描述的不同。在没有其他狼疮易感基因位点的情况下，对轻度（2X）过表达rna结合toll样受体7 （TLR7）的小鼠抗原呈递细胞（APC）和T细胞表型的分析表明，一个线索可能是核酸结合TLR的组成性刺激。这一假设及其机制将在Aim 1中进行研究。在缺乏其他狼疮易感位点的情况下，TLR7 2X过表达的小鼠是健康的，并且拥有耐受的T细胞，而TLR7 2X过表达的小鼠则发展为严重的、致命的狼疮，这是T细胞依赖的。在CD4+抗hLa特异性T细胞转移到表达TLR7 >4X的hLa转基因小鼠中，并随后分化为不同的Th和T效应细胞表型后，在CD4+抗hLa特异性T细胞中被消除的精确外周耐受机制将在Aim 2中进行评估。我们还将确定这些命运是否与特定耐受机制（如缺失和Foxp3+ Treg转化）的丧失有关，并确定IL-6和IL-21在促进该模型中致病性Th细胞分化中的作用。很少有研究研究体内DC在稳态下促进CD4+ T细胞耐受性的作用，也没有关于核酸结合核抗原的研究。在Aim 3中，我们将通过跟踪hLa转基因小鼠中抗hLa特异性T细胞的数量、表型和功能，确定B细胞、常规树突状细胞（DC）或浆细胞样DC是否对促进CD4+ T细胞对这种代表性rna结合核抗原的外周耐受性至关重要，这些细胞类型已被选择性地去除。相反，我们将确定在致病性TLR7表达的情况下，B细胞和DC在促进抗hla特异性T细胞耐受丧失和分化为致病性Th和T效应细胞类型方面的相对重要性。这些研究将确定CD4+ T细胞耐受的机制及其对系统性自身免疫性疾病中一类主要抗原的损失。系统性红斑狼疮（SLE）和干燥综合征（SS）是影响免疫系统的慢性、衰弱性自身免疫性疾病。人类和小鼠的免疫系统具有自然机制来维持自我耐受性并对感染和炎症作出反应。我们试图了解这些元素如何在稳态和炎症条件下控制CD4+ T细胞的命运和表型，以便我们更好地了解自身免疫性疾病的发展。