Antigen Presentation to Self-reactive T Cells in Human Autoimmune Diseases

人类自身免疫性疾病中抗原呈递给自身反应性 T 细胞

• 批准号: 8316141
• 负责人: Kai W Wucherpfennig
• 金额: $ 33.27万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316141
• 关键词: Affect; Affinity; Antigen Presentation; Antigen-Presenting Cells; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biochemical; CD4 Positive T Lymphocytes; Chimeric Proteins; Elements; Event; Experimental Autoimmune Encephalomyelitis; Funding; Goals; HLA-DR2 Antigen; Human; Image; Incidence; Investigation; Kinetics; Lead; Modeling; Myelin; N-terminal; Patients; Peptide antibodies; Peptide/MHC Complex; Peptides; Property; Relapse; Signal Pathway; Signal Transduction; Signaling Molecule; Stromal Cells; Structure; Synapses; T-Lymphocyte; TCR Activation; Thymus Gland; Transgenic Mice; Viral; base; immunological synapse; immunological synapse formation; lymph nodes; peripheral tolerance; synaptogenesis; targeted delivery

The goal of the project is to define the antigen presentation and T cell recognition mechanisms responsible for the activation of myelin-specific CD4 T cells in MS. During this funding period, the Pi's lab determined the crystal structure of the first human autoimmune TCR and identified an unusual TCR binding topology. Biochemical studies demonstrated a low affinity interaction of this TCR with its self-peptide/MHC complex, consistent with the suboptimal binding mode observed in the structure. Such a suboptimal binding mode may facilitate escape from tolerance induction in the thymus and periphery because the relevant antigen presenting cells express limiting quantities of self-antigen. Transgenic mice that express this TCR and the human MHC restriction element nevertheless develop spontaneous autoimmunity at a high incidence, indicating that these T cells have recognition/signaling mechanisms that at least partially compensate for the altered TCR interaction with self-peptide/MHC. Imaging studies demonstrated substantial differences in the organization of immunological synapses formed by two different myelin-specific human T cell clones compared to two anti-viral T cell clones. During the next funding period, we will determine how the altered TCR recognition properties affect the formation of immunological synapses and resulting signaling events. In Aim 1, we will define the mechanisms of immunological synapse formation by examining the kinetics of synapse formation, the recruitment of key signaling molecules, the duration of signaling as well as the mechanisms that terminate signaling by TCR internalization. Our hypothesis is that the suboptimal TCR binding properties delay TCR transport to the synapse center where TCR is internalized, thus extending the duration of the initially weaker activation signal. In Aim 2, we will examine how these changes quantitatively modify the contribution of particular signaling pathways in self-reactive versus anti-viral T cells, with the goal of identifying signaling molecules that are critical for the activation of self-reactive T cells but dispensable for anti-viral T cells. In Aim 3, we will examine whether tolerance can nevertheless be induced for such T cells by targeted delivery of the self-peptide via an antibody-peptide fusion protein to lymph node stromal cells specialized in peripheral tolerance.

该项目的目标是确定抗原呈递和T细胞识别机制 负责MS中髓鞘特异性CD 4 T细胞的激活。在此资助期间，Pi的实验室 确定了第一个人类自身免疫性TCR的晶体结构，并鉴定了一种不寻常的TCR结合， topology.生物化学研究表明，这种TCR与其自身肽/MHC的低亲和力相互作用 复合物，与结构中观察到的次优结合模式一致。这种次优的绑定 模式可能有助于逃避胸腺和外周的耐受诱导， 抗原呈递细胞表达有限量的自身抗原。表达这种TCR的转基因小鼠 而人MHC限制性元件仍然以高水平发展自发性自身免疫， 发病率，表明这些T细胞具有识别/信号传导机制，至少部分 补偿改变的TCR与自身肽/MHC的相互作用。成像研究表明 由两种不同的髓鞘特异性神经元形成的免疫突触组织的实质性差异 人T细胞克隆与两种抗病毒T细胞克隆的比较。 在下一个融资期间，我们将确定更改后的TCR确认属性如何影响 免疫突触的形成和由此产生的信号事件。在目标1中，我们将定义 免疫突触形成的机制通过检查突触形成的动力学， 关键信号分子的募集，信号传导的持续时间以及终止的机制 通过TCR内化的信号传导。我们的假设是，次优TCR结合特性延迟TCR TCR被转运到突触中心，在那里TCR被内化，从而延长了最初较弱的免疫反应的持续时间。 激活信号在目标2中，我们将研究这些变化如何定量地改变 自身反应性T细胞与抗病毒T细胞中的特定信号传导途径，目的是识别信号传导 这些分子对于自身反应性T细胞的活化至关重要，但对于抗病毒T细胞却至关重要。在 目的3，我们将研究是否仍然可以通过靶向递送诱导对这样的T细胞的耐受性 通过抗体-肽融合蛋白将自身肽的抗体-肽融合到淋巴结基质细胞中， 外周耐受性