Mechanisms of Disease Pathogenesis in Regulatory T cell Deficiency

调节性 T 细胞缺陷的疾病发病机制

• 批准号: 7999260
• 负责人: Talal Amine Chatila
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-10 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999260
• 关键词: Allergens; Allergic; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacteria; Biological Response Modifiers; Cell physiology; Cells; Dendritic Cells; Development; Disease; Disease Outcome; Disease Progression; Effector Cell; Environment; Exocytosis; Failure; General Population; Generations; Goals; Granzyme; Human; Hypersensitivity; IL2RA gene; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immune system; Immunotherapy; Individual; Induced Mutation; Inflammation; Inflammatory; Interleukin-10; Interleukin-2; Intervention; Life; Lung; Lymphoproliferative Disorders; Maintenance; Measures; Molecular; Mus; Mutation; Natural Immunity; Nature; Onset of illness; Organ; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peripheral; Play; Population; Process; Regulatory T-Lymphocyte; Role; Skin; Specificity; Surface; Syndrome; Systemic disease; T-Lymphocyte; Testing; Thymus Gland; Tissues; Transforming Growth Factor beta; Vaccines; base; cytokine; design; disorder prevention; environmental agent; forkhead protein; improved; insight; loss of function mutation; microbial; novel; novel therapeutic intervention; peripheral tolerance; precursor cell; public health relevance; research study; transcription factor

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.

描述（由申请人提供）：CD4+ FOXP3+调节t（TR）细胞对于维持外围耐受性至关重要。天然调节t（NTR）淋巴细胞是一种独特的胸腺衍生谱系。在存在TGF-β和IL-2的情况下，在抗原刺激下，可以从常规CD4+ FOXP3- T细胞从从传统的CD4+ Foxp3细胞中从头产生第二个子集。尽管NTR和ITR细胞都取决于叉子转录因子Foxp3的分化和抑制作用的表达，但两个种群在分子和功能上是不同的。在人类和小鼠中，由于FOXP3中功能突变的丧失，TR细胞的失败导致了全身自身免疫性，淋巴增殖和过敏性失调的致命疾病。 FOXP3突变还导致TR细胞前体的积累，这些前体未能区分为自身免疫性炎症过程靶向的组织中的功能性TR细胞。这些细胞被预测为自动反应性，具有高度增殖，并积极产生大量的细胞因子和颗粒酶，因此可能有助于疾病病理学。 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.该二分法是否反映了NTR和ITR细胞之间的劳动分裂，还是反映了使用不同的TR细胞效应分子（例如IL-10和CTLA-4）的利用，尚不清楚。我们的长期目标是剖析FOXP3调节的途径在免疫耐受性诱导和维持中的作用。该提案的重点是确定FOXP3缺乏症促进自身免疫性和炎症的关键细胞和分子机制。我们假设FOXP3缺乏症释放了由NTR和ITR细胞的调节失败驱动的先天性和适应性免疫反应的无限激活。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性效应细胞，该细胞有助于疾病的发病机理和组织损伤。拟议的研究将为与TR细胞缺乏症相关的疾病的发病机理提供基本见解，并将实现采用基于TR细胞干预的新型治疗方法。 公共卫生相关性：调节性T细胞（TR）缺陷障碍包括许多可遗传的免疫疾病，其特征是对疾病和环境药物（例如细菌，过敏原，疫苗）和自我组织的免疫反应不成比例的免疫反应，导致过敏性，自身免除和炎症性序列造成威胁性或致命性。许多患有TR细胞缺乏症的个体在转录因子FOXP3中具有突变，该因子控制了TR细胞的分化和功能。我们提议阐明FOXP3突变诱导疾病的机制，并探索用TR细胞挽救疾病表现的治疗能力。我们的研究将揭示新的机制，通过这种机制，免疫系统调节过敏，炎症和自身免疫性的疾病，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性疾病有关的新型治疗方法。