Mechanisms of Disease Pathogenesis in Regulatory T cell Deficiency

描述(由申请人提供)：CD4+Foxp3+调节性T(TR)细胞对维持外周耐受至关重要。自然调节性T(NTR)淋巴细胞是一种独特的胸腺来源。第二亚群诱导的Foxp3+调节性T细胞(ITR)可以从传统的CD4+Foxp3-T细胞在转化生长因子-β和IL-2存在的抗原刺激下从头产生。虽然NTR和ITR细胞的分化和抑制作用都依赖于叉头转录因子Foxp3的表达，但这两个群体在分子和功能上是不同的。在人类和小鼠中，由于Foxp3功能突变而导致的TR细胞无法分化，导致了一种致命的疾病，即全身自身免疫、淋巴细胞增殖和变态反应失调。Foxp3基因突变还会导致在自身免疫性炎症过程中靶向的组织中，未能分化为有功能的TR细胞的TR细胞前体积累。这些细胞被预测为自身反应，高度增殖，并活跃地产生大量细胞因子和颗粒酶，因此可能有助于疾病病理。我们最近对Foxp3基因缺陷小鼠的研究表明，这种疾病可以分为两个主要组成部分：一个依赖于固有免疫调节因子MyD88，涉及皮肤、肠道和肺部的粘膜表面炎症；另一个是MyD88不依赖的，表现为系统淋巴和骨髓的不受抑制的增殖。这种二分法是反映了NTR和ITR细胞之间的分工，还是反映了不同的TR细胞效应分子的利用，如IL-10和CTLA-4，目前尚不清楚。我们的长期目标是剖析Foxp3调节的通路在诱导和维持免疫耐受中的作用。这项建议的重点是确定Foxp3缺乏促进自身免疫和炎症的关键细胞和分子机制。我们假设Foxp3缺乏释放了天然免疫反应和获得性免疫反应的不受限制的激活，这是由NTR和ITR细胞的调节失败驱动的。此外，我们假设在Foxp3缺乏症中看到的流产的TR细胞前体代表了一类独特的组织特异性自身免疫效应细胞，它有助于疾病的发病机制和组织损伤。这项拟议的研究将为与受体细胞缺陷相关的疾病的发病机制提供基本的见解，并将使采用基于受体细胞的干预的新的治疗方法成为可能。 公共卫生相关性：调节性T细胞(T细胞)缺乏疾病包括一些可遗传的免疫疾病，其特征是对疾病和环境因素(如细菌、过敏原、疫苗)和自身组织的免疫反应不成比例，导致过敏、自身免疫和炎症性后遗症，危及生命或致命。许多患有TR细胞缺陷的人都有转录因子FOXP3的突变，FOXP3控制着TR细胞的分化和功能。我们建议阐明FOXP3突变导致疾病的机制，并探索用TR细胞治疗的能力来挽救疾病的表现。我们的研究将揭示免疫系统调节过敏、炎症和自身免疫疾病的新机制，并将有助于确定与这些疾病以及普通人群中更常见的变态反应性炎症和自身免疫疾病相关的新治疗方法。

DESCRIPTION (provided by applicant): CD4+Foxp3+ regulatory T (TR) cells are crucial to the maintenance of peripheral tolerance. Natural regulatory T (nTR) lymphocytes are a distinct thymus-derived lineage. A second subset of induced Foxp3+ regulatory T (iTR) cells can be generated de novo from conventional CD4+Foxp3- T cells upon antigenic stimulation in the presence of TGF-beta and IL-2. While both nTR and iTR cells are dependent on the expression of the forkhead transcription factor Foxp3 for their differentiation and suppressive action, the two populations are molecularly and functionally distinct. In both humans and in mice, the failure of TR cells to differentiate due to loss of function mutations in Foxp3 results in a lethal disease of systemic autoimmunity, lympho-proliferation and allergic dysregulation. Foxp3 mutations also result in the accumulation of TR cell precursors that have failed to differentiate into functional TR cells in tissues targeted by the autoimmune inflammatory process. These cells, which are predicted to be autoreactive, are highly proliferative and actively produce large amounts of cytokines and granzymes, and thus may contribute to disease pathology. Our recent studies on Foxp3-deficient mice revealed that the disease can be dissociated into two main components: one that is dependent on the innate immune regulator MyD88 and which involves inflammation at the mucosal surfaces in the skin, gut and lungs, and another that is MyD88-independent, manifesting as unrestrained systemic lympho- and myelo-proliferation. Whether this dichotomy reflects a division of labor between nTR and iTR cells or reflects the utilization of distinct TR cell effector molecules such as IL-10 and CTLA-4 remains unclear. Our long-term goal is to dissect the role of Foxp3-regulated pathways in the induction and maintenance of immunologic tolerance. The focus of this proposal is to identify key cellular and molecular mechanisms by which Foxp3 deficiency promotes autoimmunity and inflammation. We hypothesize that Foxp3 deficiency unleashes unrestrained activation of both the innate and the adaptive immune responses, driven by the regulatory failure of both nTR and iTR cells. Furthermore, we hypothesize that the aborted TR cell precursors seen in Foxp3 deficiency represent a unique class of tissue-specific autoimmune effector cells that contributes to disease pathogenesis and tissue damage. The proposed studies will provide fundamental insights into the pathogenesis of diseases associated with TR cell deficiency and will enable novel therapeutic approaches employing TR cell-based interventions. PUBLIC HEALTH RELEVANCE: Regulatory T cell (TR) deficiency disorders encompass a number of heritable immunological diseases characterized by disproportionate immune responses to disease and environmental agents (e.g. bacteria, allergens, vaccines) and to self tissues, leading to allergic, autoimmune and inflammatory sequelae that are life threatening or fatal. Many individuals suffering from TR cell deficiency have mutations in the transcription factor FOXP3, which controls the differentiation and the function of TR cells. We are proposing to elucidate the mechanisms by which FOXP3 mutations induce disease, and explore the capacity of therapy with TR cells to rescue the disease manifestations. Our studies would uncover novel mechanisms by which the immune system regulates diseases of allergy, inflammation and autoimmunity, and will help identify novel therapeutic approaches relevant to both these disorder and the more common allergic inflammatory and autoimmune diseases in the general population.