Virgin and memory T cells in superantigen-induced anergy

超抗原诱导的无反应中的原始 T 细胞和记忆 T 细胞

• 批准号: 6640303
• 负责人: WILLIAM T LEE
• 金额: $ 32.01万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6640303
• 关键词: CD3 molecule; T cell receptor; anergy; biological signal transduction; genetically modified animals; helper T lymphocyte; immunologic memory; laboratory mouse; leukocyte activation /transformation; membrane proteins; protein kinase C; protein structure; superantigens; tissue /cell culture

DESCRIPTION (provided by investigator): Immunological memory is critical to adaptive immunity. In the periphery, some cells can recognize self-antigen and memory development must be prevented. To understand how to generate vigorous recall responses while protecting against autoimmunity, it is essential to determine activation differences between naive and memory cells. A key question concerns how some stimuli activate cells while others induce tolerance. This is especially pertinent to memory, as memory cells are hypo-responsive or tolerant to certain agents (eg. superantigens and anti-CD3 Abs) that are strong stimulants of naive cells. This dichotomy provides strong evidence that naive and memory cells use different means to achieve a balance between immunity and tolerance. The objective of this proposal is to determine how superantigens induce tolerance in memory T cells and to better understand how improper activation of memory cells use is prevented. Thus, the planned studies will determine the activation paths of CD4 memory T cells in response to peptide antigen and superantigens. Since both antigens and superantigens may be normally encountered, understanding how they differently impact the immune system has important implications for pathology and therapy. A TCR transgenic mouse model will be used to obtain naive and memory cells bearing receptors that bind to the same peptide antigen and the same superantigen. This model will be used to test the hypothesis that superantigen induces tolerance selectively in memory T cells because of signal transduction differences in naive and memory cells. The specific aims are: 1) to identify unique signaling properties in memory T cells exposed to SEB; 2) to determine if exposure of memory cells to superantigen potentiates inhibition by negative regulators of TCR/CD3 signaling; and, 3) to determine the organizational structure of signaling proteins within the membrane of memory cells before and after exposure to superantigen. The sum of these studies will contribute to our understanding of changes occurring during the differentiation of naive cells into memory cells, will provide information on how bacterial superantigens may modulate immunity during infection, and will aid in the development of cell-specific therapies for autoimmune disease.

描述（研究人员提供）：免疫记忆对于适应性免疫至关重要。在外围，一些细胞可以识别自我抗原，并且必须防止记忆发展。要了解如何在保护自身免疫性的同时产生剧烈的回忆反应，必须确定幼稚和记忆细胞之间的激活差异。一个关键问题涉及一些刺激如何激活细胞，而另一些刺激如何诱导耐受性。这尤其与记忆有关，因为记忆细胞对某些幼体细胞的强兴奋剂（例如，超级抗原和抗CD3 ABS）具有低反应性或耐受性。这种二分法提供了有力的证据，表明天真和记忆细胞使用不同的手段来实现免疫和耐受性之间的平衡。该建议的目的是确定超抗原如何诱导记忆T细胞中的公差，并更好地理解如何阻止记忆细胞使用不当的激活。因此，计划的研究将确定响应肽抗原和超抗原的CD4记忆T细胞的激活路径。由于通常可以遇到抗原和超抗原，因此了解它们对免疫系统的不同影响对病理和治疗具有重要意义。 TCR转基因小鼠模型将用于获得与同一肽抗原和相同超抗原结合的幼稚和带有结合的记忆细胞。该模型将用于测试以下假设，即由于幼稚和记忆细胞的信号转导差异，超抗原在记忆T细胞中有选择地诱导耐受性。具体目的是：1）在暴露于SEB的记忆T细胞中识别独特的信号传导特性； 2）确定记忆细胞是否会暴露于TCR/CD3信号的负调节剂中抑制超抗原电位； 3）在暴露于超抗原之前和之后，确定记忆细胞膜内信号蛋白的组织结构。这些研究的总和将有助于我们理解幼稚细胞在记忆细胞中分化过程中发生的变化，将提供有关细菌超抗原在感染过程中如何调节免疫力的信息，并有助于开发自身免疫性疾病的细胞特异性疗法。