The immunobiology of CD4+ CD25+ T regulatory cells

CD4 CD25 T 调节细胞的免疫生物学

• 批准号: 8384876
• 负责人: Thomas R Malek
• 金额: $ 35.96万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384876
• 关键词: Address; Affinity; Agreement; Allogenic; Antigens; Area; Autoantigens; Autoimmune Diseases; Autoimmunity; Biological Models; Biological Response Modifiers; Bone Marrow; Celiac Disease; Cells; Clinical; Clinical Trials; Data; Drug usage; Ensure; Etiology; Excision; Genetic Polymorphism; Graft Rejection; Grant; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; IL2RA gene; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunobiology; Immunosuppression; Immunotherapy; Infection; Insulin-Dependent Diabetes Mellitus; Interleukin-2; Knowledge; Laboratories; Link; Modeling; Multiple Sclerosis; Mus; Mutation; Peptide/MHC Complex; Peripheral; Population; Predisposition; Production; Reaction; Regulatory T-Lymphocyte; Reporting; Research Design; Resistance; Rheumatoid Arthritis; Self Tolerance; Specificity; Stem cell transplant; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Testing; Therapeutic; Tissues; Work; autoreactive T cell; base; chemotherapy; clinically relevant; conditioning; genetic risk factor; imprint; in vivo Model; interest; mouse model; novel; prevent; public health relevance; reconstitution; response; systemic autoimmune disease; tumor

DESCRIPTION (provided by applicant): There is considerable interest in understanding the basic immunobiology of T regulatory (Treg) cells as they offer a means to inhibit unwanted immune responses that occur during autoimmune disease or as a consequence of hematopoietic stem cell transplantation (HSCT) or tissue transplant rejection reactions. An important area of Treg cell immunobiology that is poorly understood concerns the antigen specificity of these suppressor T cells in maintaining peripheral self-tolerance. We have developed in vivo model systems that permits direct examination of TCR diversity and specificity as it relates to control of autoimmune disease. In one model, Treg cells are adoptively transferred into IL-2Rb-/- mice, which develop rapid lethal systemic autoimmunity due to their failed production of effective Treg cells. These donor Treg cells fully prevent this autoimmunity and provide a defined population of therapeutic Treg cells to examine issues regarding TCR diversity and specificity. In another clinically relevant model, host Treg cells that survive lethal conditioning after HSCT function to suppress autoreactive donor-derived T cells. We have used these models to address questions concerning the importance of high TCR diversity of Treg cells for self-tolerance. Our initial work shows that in settings of rampant breakdown of immune tolerance, control of autoimmunity is achieved by only a fraction of the available Treg TCR repertoire that was accompanied by substantial peripheral reshaping. Ultimately, too severe constraints on Treg TCR diversity sometimes resulted in autoimmunity. This latter finding is consistent with the hypothesis that TCR repertoire skewing represents a potential intrinsic Treg cell deficit that causes autoimmunity. This proposal plans to build on these data and to exploit the unique features of these models to more precisely define the requirements for Treg TCR diversity and specificity in control of autoimmunity. An important related objective is to investigate mechanisms operative that contribute to peripheral modulation of Treg specificities. To address these issues we propose the following specific aims:1) To further characterize the relevance of TCR diversity in Foxp3+ regulatory T cells by evaluating the efficacy and durability of Treg cells with limited diversity to suppress autoimmunity; 2) to test the requirement for homeostatic mechanisms to drive peripheral reshaping of the Treg TCR repertoire; and 3) to evaluate the effect of altering TCR selection of Treg and autoreactive T cells on peripheral self-tolerance and Treg TCR repertoire reshaping. Completion of these aims should expand our knowledge concerning the selection and diversity of the Treg TCR as it directly relates to the mechanisms by which these cells maintain self-tolerance. This proposal has the potential to impact the field by providing new and essential information that is likely critical for application of Treg cells in immunotherapy to the multitude of scenarios where one wish to inhibit unwanted immune responses.

描述（由申请人提供）：人们对理解T调节（Treg）细胞的基本免疫生物学非常感兴趣，因为它们提供了一种抑制自身免疫疾病期间或作为造血干细胞移植（HSCT）或组织移植排斥反应的结果发生的不需要的免疫应答的方法。Treg细胞免疫生物学的一个重要领域是了解甚少的，涉及这些抑制性T细胞在维持外周自身耐受中的抗原特异性。我们已经开发了体内模型系统，其允许直接检查TCR多样性和特异性，因为其涉及自身免疫性疾病的控制。在一个模型中，Treg细胞过继转移到IL-2 Rb-/-小鼠中，由于它们不能产生有效的Treg细胞，这些小鼠产生快速致死的全身性自身免疫。这些供体Treg细胞完全防止这种自身免疫，并提供了确定的治疗性Treg细胞群，以检查关于TCR多样性和特异性的问题。在另一个临床相关模型中，在HSCT后存活致死条件作用的宿主Treg细胞发挥抑制自身反应性供体来源的T细胞的功能。我们已经使用这些模型来解决关于Treg细胞的高TCR多样性对于自身耐受性的重要性的问题。我们的初步工作表明，在免疫耐受的猖獗崩溃的设置中，仅通过一小部分可用的Treg TCR库来实现对自身免疫的控制，所述Treg TCR库伴随着大量的外周重塑。最终，对Treg TCR多样性的过于严格的限制有时会导致自身免疫。后一发现与TCR库偏斜代表导致自身免疫的潜在内在Treg细胞缺陷的假设一致。该提案计划建立在这些数据的基础上，并利用这些模型的独特功能，以更精确地定义控制自身免疫的Treg TCR多样性和特异性的要求。一个重要的相关目标是研究有助于外周调节Treg特异性的机制。为了解决这些问题，我们提出了以下具体目标：1）通过评估具有有限多样性的Treg细胞抑制自身免疫的功效和持久性来进一步表征Foxp 3+调节性T细胞中TCR多样性的相关性; 2）测试驱动Treg TCR库的外周重塑的稳态机制的需求;和3）评估改变Treg和自身反应性T细胞的TCR选择对外周自身耐受性和Treg TCR库重塑的影响。这些目标的完成应该扩大我们的知识，关于Treg TCR的选择和多样性，因为它直接涉及这些细胞保持自身耐受性的机制。该提案有可能通过提供新的和必要的信息来影响该领域，这些信息对于Treg细胞在免疫治疗中应用于希望抑制不需要的免疫反应的多种情况可能是至关重要的。