Mechanisms of Disease Pathogenesis in Regulatory T cell Deficiency

描述（由申请方提供）：CD 4 + Foxp 3+调节性T（TR）细胞对于维持外周耐受性至关重要。天然调节性T（nTR）淋巴细胞是一种独特的胸腺衍生谱系。诱导的Foxp 3+调节性T（iTR）细胞的第二亚群可以在TGF-β和IL-2存在下经抗原刺激从常规CD 4 + Foxp 3- T细胞从头产生。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Foxp 3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Foxp 3中功能突变的丧失导致TR细胞分化失败，导致全身性自身免疫、淋巴增殖和过敏性调节异常的致命疾病。Foxp 3突变还导致TR细胞前体的积累，这些前体在自身免疫炎症过程靶向的组织中未能分化成功能性TR细胞。这些被预测为自身反应性的细胞是高度增殖的，并且活跃地产生大量的细胞因子和颗粒酶，因此可能有助于疾病病理。我们最近对Foxp 3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：一个依赖于先天免疫调节剂MyD 88，涉及皮肤，肠道和肺部粘膜表面的炎症，另一个是MyD 88独立的，表现为不受限制的全身淋巴细胞和骨髓增殖。这种二分法是否反映了nTR和iTR细胞之间的分工或反映了不同TR细胞效应分子如IL-10和CTLA-4的利用仍不清楚。我们的长期目标是剖析Foxp 3调节通路在诱导和维持免疫耐受中的作用。该提案的重点是确定Foxp 3缺陷促进自身免疫和炎症的关键细胞和分子机制。我们假设Foxp 3缺陷释放了先天性和适应性免疫反应的无限制激活，由nTR和iTR细胞的调节失败驱动。此外，我们假设在Foxp 3缺陷中看到的流产的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，其有助于疾病的发病机制和组织损伤。拟议的研究将提供与TR细胞缺乏相关的疾病的发病机制的基本见解，并将使新的治疗方法采用TR细胞为基础的干预措施。 公共卫生相关性：调节性T细胞（TR）缺乏症包括许多遗传性免疫疾病，其特征在于对疾病和环境因子（例如细菌、过敏原、疫苗）和自身组织的不成比例的免疫应答，导致威胁生命或致命的过敏性、自身免疫性和炎性后遗症。许多患有TR细胞缺陷的个体在转录因子FOXP 3中具有突变，该转录因子FOXP 3控制TR细胞的分化和功能。我们建议阐明FOXP 3突变诱导疾病的机制，并探索TR细胞治疗挽救疾病表现的能力。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过敏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.