T Cell Tolerance & Autoimmunity to Nuclear Antigen La

T细胞耐受性

• 批准号: 7583751
• 负责人: A Darise Farris
• 金额: $ 27.83万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-22 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7583751
• 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; Helper-Inducer T-Lymphocyte; Hematopoietic; Human; Immune Tolerance; Immune system; Infection; Inflammation; Inflammatory; 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; Relative (related person); Role; Self Tolerance; Sjogren' s Syndrome; Structure of germinal center of lymph node; Syndrome; System; Systemic Lupus Erythematosus; T-Cell Receptor; T-Lymphocyte; Toll-like receptors; Transgenic Mice; cell type; clinically relevant; design; disease phenotype; human TLR7 protein; in vivo; lupus-like; male; novel; overexpression; public health relevance; systemic autoimmune disease

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结合核抗原是针对全身自身免疫性疾病的主要自身抗原，包括全身性红斑狼疮（SLE）和SJVGREN综合征（SS）。尽管众所周知，在Murine lupus模型中，T助手（Th）细胞对疾病至关重要，但在系统自身免疫性的情况下通常介导对RNA结合核抗原的免疫学耐受性以及在系统自身免疫性的情况下被违反的特定耐受性途径的机制。我们开发了第一个也是唯一的小鼠转基因，用于RNA结合核抗原特异性TCR T细胞受体（TCR），以描绘导致T细胞耐受性的特定机制。通过将特异性的T细胞转移到临床相关的人LA/SS-B抗原（HLA）中，将其转移到小鼠转基因中，以进行HLA的生理表达并跟踪其数量，表型和功能，我们将描述导致周围T细胞耐受性的机制（AIM 1）。初步研究表明，这些T细胞采用的耐受性模式取决于受体中的抗原呈递水平，并且在该系统中促进Foxp3+调节性T细胞的体内提示与先前描述的抗原提示不同。在没有其他狼疮易感基因座的情况下，对小鼠（2x）过表达的RNA结合受体7（TLR7）的抗原呈递细胞（APC）和T细胞表型的分析表明，一种提示可能是一种提示是可以是对核酸结合TLR的组成型刺激。该假设及其机制将在AIM 1中进行研究。小鼠在没有其他狼疮易感性基因座的情况下过表达TLR7 2X是健康的，并且具有耐耐受性的T细胞，而过表达TLR7> 4x的小鼠高于正常的tlr7> 4倍，而正常的lupus则会产生严重的致命性lupus，这是T细胞依赖于T细胞的。转移到HLA转基因小鼠中，这些精确的周围耐受性机制在CD4+抗HLA特异性T细胞中被废除，它们表达TLR7> 4X及其随后的分化为不同的Th和T效应细胞表型，在AIM 2中评估这些命运是否与特定耐受性的损失相关。在该模型中促进致病性TH细胞分化时，IL-6和IL-21的of。很少有研究研究了体内DC在稳定状态下促进CD4+ T细胞耐受性中的作用，并且尚未描述过这种对核酸结合核抗原的研究。在AIM 3中，我们将确定B细胞，常规的树突状细胞（DC）或铂类固醇DC是否对于促进CD4+ T细胞的外围耐受性是否针对该代表性的RNA结合核抗原，遵循抗HLA传输小鼠中抗HLA特异性T细胞的数量，表型和功能，这些抗原在HLA转换鼠标中已选择性地描述了这些细胞中这些细胞的型号。相反，我们将确定B细胞和直流在促进耐受性丧失以及在致病性TH和T效应细胞类型中促进耐受性丧失以及在致病性（> 4X）TLR7表达的情况下的相对重要性。这些研究将定义CD4+ T细胞耐受性的机制及其对全身自身免疫性疾病的主要抗原的损失。公共卫生相关性系统性红斑狼疮（SLE）和Sjogren综合征（SS）是长期的，使影响免疫系统的自身免疫性疾病令人衰弱。人类和小鼠的免疫系统具有自然机制，旨在维持自我耐受并应对感染和炎症。我们试图了解这些元素如何控制稳态和炎症条件下的CD4+ T细胞命运和表型，以便我们可以更好地了解自身免疫性疾病的发展。