Cbl-b in T Cell Activation and Autoimmunity

Cbl-b 在 T 细胞激活和自身免疫中的作用

• 批准号: 8493776
• 负责人: JIAN ZHANG
• 金额: $ 35.71万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-08 至 2016-06-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8493776
• 关键词: Accounting; Adaptor Signaling Protein; Address; Adoptive Transfer; Affect; Asthma; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; B7/CTLA-4 interaction; Binding; Biological Process; C-terminal; CD28 gene; Cell Differentiation process; Cells; Data; Development; Equilibrium; Extrinsic asthma; Family; Figs - dietary; Fingers; Gatekeeping; Gene Targeting; Generations; IL2RA gene; Immunity; In Vitro; Interleukin-4; Lead; Ligation; Lymphoma; Maintenance; Modeling; Molecular; Mus; Pathway interactions; Peripheral; Phosphotyrosine; Predisposition; Process; Production; Proline-Rich Domain; Protein Family; Protein Tyrosine Kinase; Proteins; Receptor Signaling; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Resistance; Signal Transduction; Signaling Protein; Site; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Transfection; Tyrosine; UBA Domain; Ubiquitin; Ubiquitin-Conjugating Enzymes; Ubiquitination; airway inflammation; allergic airway inflammation; anergy; base; in vitro activity; in vivo; interest; prevent; protein degradation; public health relevance; response; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Casitas-B-lineage lymphoma protein-b (Cbl-b) is an adaptor protein and RING finger domain-type E3 ubiquitin (Ub) ligase, and has been shown to be important for the maintenance of a balance between immunity and tolerance. Previously, we demonstrated that CD28 costimulation potentiates TCR-induced Cbl-b ubiquitination and degradation, whereas CTLA-4-B7 interaction is required for Cbl-b re-expression. These observations indicate that CD28 and CTLA-4 tightly regulate Cbl-b expression which is critical for establishing the threshold for T cell activation and tolerance. In strong support of this notion, Cbl-b-/- T cells are resistant to anergy induction in vitro and in vivo. Indeed, Cbl-b-/- mice are highly susceptible to autoimmunity. Further studies reveal that Cbl-b not only down- regulates T cell activation, but also selectively inhibits T helper 2 (Th2) differentiation and allergic airway inflammation. Intriguingly, Cbl-b favors peripheral conversion of naove CD4? T cells into CD4???? Tregs (iTregs) in vitro. Although Cbl-b-/- CD4? naturally-occurring Tregs (nTregs) display normal suppressive activity in vitro, Cbl-b-/- CD4? effector T cells (Teffs) are resistant to regulation by nTregs which is possibly due to increased production of IL-4. At the molecular levels, Cbl-b selectively associates with Stat-6, an important transcription factor involved in Th2 cell differentiation, upon IL-4 ligation and may inhibit Th2 differentiation by targeting Stat-6 for degradation. These processes are heightened in the TCR signaling. Furthermore, Cbl-b facilitates iTreg generation by inhibiting PI3-K/Akt activation. Based upon the above data, we hypothesize that Cbl-b targets Stat-6 for ubiquitination and facilitate iTreg generation, thus inhibiting Th2 responses and allergic airway inflammation. To test this hypothesis, we will investigate: 1) whether Cbl-b inhibits Th2 responses by targeting Stat-6 for ubiquitination, thus suppressing alleric airway inflammation; and 2) whether and how Cbl-b regulates the development of iTregs in vivo, therefore modulating Th2 responses and allergic airway inflammation. The specific aims of this proposal will address fundamental question: how does Cbl-b regulate its target substrates/pathways related to its biological functions. A better understanding of cellular and molecular mechanisms of Cbl-b biological functions may lead to potential therapeutic approaches for autoimmune diseases and allergic asthma.

描述（由申请人提供）：casitas-b-linege淋巴瘤蛋白-B（CBL-B）是一种适配器蛋白和环形域型型型型E3泛素（UB）连接酶，并且已证明对于维持免疫和耐受性之间的平衡很重要。以前，我们证明CD28共刺激增强了TCR诱导的CBL-B泛素化和降解，而CTLA-4-B7相互作用是CBL-B重新表达所必需的。这些观察结果表明，CD28和CTLA-4严格调节CBL-B表达，这对于确定T细胞激活和耐受性的阈值至关重要。为了强烈支持这一概念，CBL-B - / - T细胞对体外和体内的反感诱导性具有抗性。实际上，CBL-B - / - 小鼠非常容易受到自身免疫性的影响。进一步的研究表明，CBL-B不仅调节T细胞的激活，而且还可以选择性地抑制T助手2（TH2）分化和过敏性气道炎症。有趣的是，cbl-b有利于naove cd4的外围转换？ T细胞进入CD4 ???? Tregs（ITREGS）体外。虽然CBL-B - / - CD4？天然发生的Treg（NTREG）在体外表现出正常的抑制活性，CBL-B-/ - CD4？效应T细胞（TEFF）对NTREG的调节有抵抗力，这可能是由于IL-4的产生增加所致。在分子水平上，CBL-B选择性地将STAT-6（IL-4连接后Th2细胞分化涉及的重要转录因子）相关联，并且可以通过将Stat-6靶向降解来抑制Th2分化。这些过程在TCR信号传导中得到了增强。此外，CBL-B通过抑制PI3-K/AKT激活来促进ITREG的生成。基于上述数据，我们假设CBL-B靶标STAT-6用于泛素化并促进ITREG的产生，从而抑制TH2反应和过敏性气道炎症。为了检验这一假设，我们将研究：1）CBL-B是否通过靶向Stat-6来抑制TH2反应，从而抑制了迫切气道炎症； 2）CBL-B是否以及如何调节体内ITREGS的发展，因此调节TH2反应和过敏性气道炎症。该提案的具体目的将解决基本问题：CBL-B如何调节其目标底物/途径与其生物学功能相关。更好地了解CBL-B生物学功能的细胞和分子机制可能会导致自身免疫性疾病和过敏性哮喘的潜在治疗方法。