The immunobiology of CD4+ CD25+ T regulatory cells

描述（由申请人提供）：人们对了解T调节细胞（Treg）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性疾病或造血干细胞移植（HSCT）或组织移植排斥反应引起的不必要免疫反应的方法。Treg细胞免疫生物学的一个重要领域是这些抑制性T细胞在维持外周自我耐受性方面的抗原特异性。我们已经开发了体内模型系统，可以直接检查TCR的多样性和特异性，因为它与自身免疫性疾病的控制有关。在一种模型中，将Treg细胞过继转移到IL-2Rb-/-小鼠体内，IL-2Rb-/-小鼠由于无法产生有效的Treg细胞而产生快速致死性全身自身免疫。这些供体Treg细胞完全可以预防这种自身免疫，并提供了一个确定的治疗性Treg细胞群体，以检查有关TCR多样性和特异性的问题。在另一个临床相关的模型中，宿主Treg细胞在造血干细胞移植后存活下来，抑制自身反应性供体来源的T细胞。我们使用这些模型来解决有关Treg细胞高TCR多样性对自我耐受的重要性的问题。我们的初步工作表明，在免疫耐受严重破坏的情况下，只有一小部分可用的Treg TCR库伴随着大量的外周重塑才能实现自身免疫的控制。最终，对Treg TCR多样性过于严格的限制有时会导致自身免疫。后一项发现与假设一致，即TCR库倾斜代表潜在的内在Treg细胞缺陷，导致自身免疫。本提案计划以这些数据为基础，利用这些模型的独特特征，更精确地定义自身免疫控制中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有效性和持久性，进一步表征Foxp3+调节性T细胞中TCR多样性的相关性；2)测试对驱动Treg TCR库外围重塑的稳态机制的需求；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。这些目标的完成将扩大我们对Treg TCR的选择和多样性的认识，因为它直接关系到这些细胞维持自我耐受性的机制。这一建议有可能通过提供新的和必要的信息来影响该领域，这些信息可能对Treg细胞在免疫治疗中的应用至关重要，因为人们希望在多种情况下抑制不必要的免疫反应。

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. PUBLIC HEALTH RELEVANCE: The utilization of Treg cells in immunotherapy is considered a promising new avenue for highly specific and potentially non-toxic suppression of unwanted immune responses that occur during debilitating autoimmune diseases. Successful therapy with Treg cells requires information concerning the proper TCR specificities that optimally suppress autoreactive T cells. The proposed studies are designed to exploit our novel mouse models to advance understanding concerning the requirement for Treg TCR diversity and specificity in control of autoreactive T cells. The immune system must be continually rebalanced after infections, HSCT, or the use of drugs for immunosuppression and tumor chemotherapy. Indeed, TCR repertoire reshaping occurs for Treg cells after HSCT. Thus, the mechanisms involved in selection and reshaping of the Treg TCR repertoire are fundamental to understand the basis of immune tolerance and susceptibility to autoimmunity and relevant to a widely used clinical therapy. Besides these issues, a rare form of systemic autoimmune disease has been linked to genetic defects in the human IL-2R. Polymorphism in IL-2, IL-2Ra and IL-2Rb are prominent genetic risk factors for a variety of human autoimmune diseases, including multiple sclerosis, type 1 diabetes, rheumatoid arthritis and celiac disease. The IL-2Rb-deficient model used in some of these studies also has an important link to human autoimmunity. Understanding the factors that reverse autoimmunity in the IL-2Rb- deficient model may also provide new information concerning the etiology and potential therapy that may be generally common to several human autoimmune diseases.