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性至关重要。自然调节性T淋巴细胞（nTR）是一个独特的胸腺衍生谱系。第二种诱导的Foxp3+调节性T （iTR）细胞可以在tgf - β和IL-2存在的抗原刺激下从传统的CD4+Foxp3- T细胞重新生成。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功能突变缺失导致TR细胞分化失败，导致系统性自身免疫、淋巴细胞增殖和过敏性失调的致命疾病。Foxp3突变还导致自身免疫性炎症过程靶向组织中无法分化为功能性TR细胞的TR细胞前体的积累。据预测，这些细胞具有自身反应性，具有高度增殖能力，并积极产生大量细胞因子和颗粒酶，因此可能导致疾病病理。我们最近对foxp3缺陷小鼠的研究表明，该疾病可以分解为两个主要组成部分：一个依赖于先天免疫调节剂MyD88，涉及皮肤、肠道和肺部粘膜表面的炎症，另一个不依赖于MyD88，表现为不受限制的全身淋巴和骨髓增生。这种分化是否反映了nTR和iTR细胞之间的分工，还是反映了不同的TR细胞效应分子如IL-10和CTLA-4的利用尚不清楚。我们的长期目标是剖析foxp3调控通路在诱导和维持免疫耐受中的作用。本提案的重点是确定Foxp3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Foxp3缺陷释放了先天和适应性免疫反应的无限制激活，这是由nTR和iTR细胞的调节失败驱动的。此外，我们假设在Foxp3缺陷中观察到的流产的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，它们有助于疾病的发病和组织损伤。拟议的研究将为与TR细胞缺乏症相关的疾病的发病机制提供基本见解，并将使基于TR细胞干预的新治疗方法成为可能。

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.