Role of CD4+ regulatory T cells in T cell vaccination

CD4 调节性 T 细胞在 T 细胞疫苗接种中的作用

• 批准号: 6804756
• 负责人: JINGWU Z ZHANG
• 金额: $ 34.8万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804756
• 关键词: B lymphocyte; T lymphocyte; antiinflammatory agents; autoimmunity; cell cell interaction; cell proliferation; clinical research; clinical trials; clone cells; cytokine receptors; helper T lymphocyte; human subject; human tissue; immunization; inflammation; interleukin 2; leukocyte activation /transformation; leukocyte count; lymphocyte; major histocompatibility complex; monocyte; multiple sclerosis; myelin basic proteins; patient oriented research; protein structure function; recombinant proteins; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): T cell vaccination (TCV) is proven to be an effective means of regulating autoreactive T cells through regulatory network of CD8+ and CD4+ T cell subsets. Both regulatory T cell (Treg) subsets are thought to contribute to suppression of circulating myelin basic protein (MBP)-reactive T cells and some clinical improvement seen in clinical trials in multiple sclerosis (MS). CD8+ T cells induced by TCV belong to cytotoxic anti-idiotypic T cell subset interacting with the T cell receptors of MBP-reactive T cells. In contrast, the nature of CD4+ Treg subset is poorly understood. They exhibit unique regulatory properties through the production of IL-10 but not Th1 cytokines, resulting in a potent inhibitory effect on MBP-reactive T cells. Their reactivity and inhibition appear restricted to activated T cells, regardless of antigen specificity, but not resting cells. Further evidence suggests that CD4+ Treg cells induced by TCV react with and are activated by endogenously processed IL-2 receptor alpha chain (IL-2Ra). These findings have begun to unfold the unique properties and functional role of CD4+ Treg induced by TCV in the regulation of autoreactive T cells in humans. In this study, we propose to investigate the central hypothesis that TCV induces the activation and in vivo expansion of CD4+ Treg cells through interaction with IL-2Ra expressed on activated autoreactive T cells and that IL-2Ra has an anti-inflammatory property by inducing a CD4+ Treg response. The study has three specific aims. In Aim 1, the role of TCV in in vivo expansion of pre-existing CD4+ Treg pool will be determined by examining the precursor frequency of CD4+ Treg cells in peripheral blood mononuclear cells (PBMC) derived from MS patients before and after TCV. The results will be analyzed to correlate with serum cytokines, the frequency of MBP-reactive T cells and other parameters in the same patients. Cloned CD4+ Treg cell lines will be characterized in detail to address their functional role and heterogeneity, reactivity and MHC restriction, mode of induction and interaction with various target T cells. Aim 2 will focus on the reactivity pattern and interaction of CD4+ Treg cells with IL-2Ra using well-characterized T cell lines in two experimental systems by testing the reactivity of CD4+ Treg T cell lines to endogenously processed IL-2Ra using autologous B cell transfectants and to soluble IL-2Rot using recombinant protein in functional assays. Additional experiments will delineate the region(s) of IL-2Ra preferably recognized by CD4+ Treg using target cells transfected with truncated gene segments and overlapping peptides. In Aim 3, we will define the potency and specificity of IL-2Rc_ protein as a specific agent for the direct induction of CD4+ Treg cell response in PBMC as well as the role of TCV in this process by analyzing the T cell responses, as the frequency of reactive CD4+ Treg cells, to IL-2R(x protein or preferably recognized peptides in pre- and postvaccination PBMC and those of controls. Parallel experiments are designed to evaluate the inhibitory effect of IL-2Ra on MBP-reactive T cell responses through its intrinsic property of inducing CD4+ Treg cell response in MBP-primed PBMC cultures. The overall results will provide new insights into the role of IL- 2Ro_ in regulation of pro-inflammatory T cell response in autoimmune conditions.

描述（由申请人提供）：T细胞疫苗接种（TCV）被证明是通过CD8+和CD4+ T细胞子集调节自动反应性T细胞的有效手段。两种调节性T细胞（TREG）亚群都被认为有助于抑制循环髓磷脂碱性蛋白（MBP） - 反应性T细胞，并且在多发性硬化症（MS）的临床试验中看到了一些临床改善。由TCV诱导的CD8+ T细胞属于细胞毒性抗IDiotypic T细胞亚群与MBP反应性T细胞的T细胞受体相互作用。相反，CD4+ Treg子集的性质知之甚少。它们通过产生IL-10而非Th1细胞因子表现出独特的调节性能，从而对MBP反应性T细胞产生有效的抑制作用。它们的反应性和抑制作用似乎仅限于活化的T细胞，而不论抗原特异性如何，但不静止。进一步的证据表明，由TCV诱导的CD4+ Treg细胞与内源加工的IL-2受体α链（IL-2RA）一起激活并激活。这些发现已开始展现由TCV引起的CD4+ Treg在人类自动反应性T细胞调节中的独特特性和功能作用。在这项研究中，我们建议研究中心假设，即TCV通过与激活的自动反应性T细胞表达的IL-2RA相互作用来诱导CD4+ Treg细胞的激活和体内扩展，并且IL-2RA通过诱导CD4+ Treg响应诱导抗炎特性。该研究具有三个特定的目标。在AIM 1中，TCV在预先存在的CD4+ Treg池的体内扩展中的作用将通过检查TCV前后的MS患者的外周血单核细胞（PBMC）中CD4+ Treg细胞的前体频率。将分析结果以与同一患者的血清细胞因子，MBP反应性T细胞的频率和其他参数相关。克隆的CD4+ Treg细胞系将进行详细表征，以解决其功能作用和异质性，反应性和MHC限制，诱导方式以及与各种靶T细胞的相互作用。 AIM 2通过在两个实验系统中使用良好的T细胞系的CD4+ Treg细胞与IL-2RA的反应性模式和相互作用，通过测试CD4+ Treg T细胞系的反应性，使用自体B细胞转染剂和使用重组蛋白在功能疗法中使用自体B细胞转染剂和使用自体B细胞转染剂和可溶性IL-2ROT进行内源处理的IL-2RA。其他实验将使用用截短的基因段和重叠肽转染的靶细胞来描述CD4+ Treg优选识别IL-2RA的区域。 In Aim 3, we will define the potency and specificity of IL-2Rc_ protein as a specific agent for the direct induction of CD4+ Treg cell response in PBMC as well as the role of TCV in this process by analyzing the T cell responses, as the frequency of reactive CD4+ Treg cells, to IL-2R(x protein or preferably recognized peptides in pre- and postvaccination PBMC and those of controls. Parallel实验旨在评估IL-2RA对MBP反应性T细胞反应的抑制作用，其内在特性在MBP培养的PBMC培养物中诱导CD4+ Treg细胞响应的固有特性，总体结果将为IL-2RO_在自动膜中的促进中的作用提供新的见解。