Developmental regulation of CD8 class I MHC binding

CD8 I 类 MHC 结合的发育调控

• 批准号: 6765878
• 负责人: STEPHEN C JAMESON
• 金额: $ 29.19万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6765878
• 关键词: CD8 molecule; MHC class I antigen; T cell receptor; antigen presentation; cytotoxic T lymphocyte; developmental immunology; glycosylation; leukocyte activation /transformation; lymphopoiesis; protein binding; receptor expression; tissue /cell culture

DESCRIPTION (provided by the applicant): CD8 binds Class I MHC molecules-in this way CD8 can act as a coreceptor with the T cell receptor (TCR), for recognition of specific peptide/MHC ligands. However, CD8 also acts as an adhesion receptor for Class I MHC ligands without involvement of the TCR (this is called non-cognate Class I MHC binding). Our preliminary data show that the CD8 mediated non-cognate Class I binding changes radically during I cell maturation. This has profound implications for Cd8-mediated regulation of cytotoxic I cell (CTL) differentiation and immune reactivity. In this proposal, we will explore how CD6 mediated non-cognate Class I binding is regulated both in development and in CTL activation. We also study the nature of non-cognate Class I binding, in particular the role of the CD8beta chain. In Aim 1, we will test how changes in T cell glycosylation impacts on non-cognate Class I interactions. This builds on our preliminary data suggesting that the extent of cell surface sialylation alters the capacity of CD8 molecules to bind Class I ligands. In addition, we explore the role of ICR expression levels and a form of CD8 (called CD8 alpha prime) expressed only in immature thymocytes. In Aim 2, we study regulation of non-cognate CD8-Class I binding during CTL activation, in part to determine whether it is regulated by the same factors which control CD8 binding in development In addition, we explore the functional significance of non-cognate Class I binding on CTL cytolytic activity, a measure of the functional relevance of this binding. Finally in Aim 3, we focus on the role of CD8beta, the second chain of the CD8 molecule. We will determine whether CD8beta plays a unique role in non-cognate Class I binding and in affecting the specific contact sites on the Class I MHC molecule to which CD8 binds.

描述（由申请人提供）：CD 8结合I类MHC分子-以这种方式，CD 8可以作为T细胞受体（TCR）的辅助受体，用于识别特异性肽/MHC配体。然而，CD 8也充当I类MHC配体的粘附受体，而不涉及TCR（这称为非同源I类MHC结合）。我们的初步数据显示，CD 8介导的非同源I类结合在I细胞成熟过程中发生根本性变化。这对Cd 8介导的细胞毒性I细胞（CTL）分化和免疫反应性的调节具有深远的意义。在这个建议中，我们将探讨如何CD 6介导的非同源I类结合调节发展和CTL活化。我们还研究了非同源I类结合的性质，特别是CD 8 β链的作用。 在目标1中，我们将测试T细胞糖基化的变化如何影响非同源I类相互作用。这建立在我们的初步数据的基础上，表明细胞表面唾液酸化的程度改变了CD 8分子结合I类配体的能力。此外，我们探讨了ICR表达水平和一种仅在未成熟胸腺细胞中表达的CD 8（称为CD 8 alpha prime）的作用。 在目的2中，我们研究了CTL活化过程中非同源CD 8-I类结合的调节，部分是为了确定它是否受到控制CD 8结合的相同因素的调节。此外，我们探索了非同源I类结合对CTL细胞溶解活性的功能意义，这是一种衡量这种结合的功能相关性的方法。 最后，在目标3中，我们关注CD 8 β（CD 8分子的第二条链）的作用。我们将确定CD 8 β是否在非同源I类结合和影响CD 8结合的I类MHC分子上的特异性接触位点中发挥独特作用。