IMMUNE RESPONSES BY TCR VB SPECIFIC CD8 T CELLS

TCR VB 特异性 CD8 T 细胞的免疫反应

基本信息

批准号：
6169723
负责人：
HONG JIANG
金额：
$ 12.09万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2001-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6169723
关键词：
CD antigens MHC class I antigen T cell receptor cell differentiation cytotoxic T lymphocyte experimental allergic encephalomyelitis gene targeting helper T lymphocyte histocompatibility antigens laboratory mouse leukocyte activation /transformation lymphokines myelin basic proteins passive immunization protein biosynthesis tissue /cell culture transfection

项目摘要

Interactions mediated by T cell receptors (TCRs) expressed on different T cell subsets may play a role in immunoregulation. To investigate this idea we studied the regulation of superantigen induced TCR restricted responses. We asked whether the in vivo regulation of CD4+Vbeta8+ T cells following SEB injection is controlled by CD8+ T cells. We found that in mice depleted of CD8+ cells by treatment with monoclonal anti-CD8 antibody or in CD8+ T cell deficient beta2 M-/- mice, the delayed downregulation of CD4+Vbeta8+ T cells below baseline is not observed. Moreover, following SEB administration CD8+ T cells emerge which preferentially kill subpopulations of activated CD4+Vbeta8+ but not CD4+Vbeta8- T cells in vitro. This TCR Vbeta specific cytotoxicity is dependent on beta2 microglobulin and is inhibited by antisera specific for Qa-1 but not by antibody to MHC class I-a. Interestingly, SEB activation increases Qa-1 surface expression and renders T cells susceptible to lysis. These data suggest that the specificity of immune regulation may involve CD8+ T cell recognition of TCR Vbeta determinants and Qa-1 molecules expressed on antigen activated CD4+ T cells. In the first specific aim of this grant we will define the molecular targets of the Vbeta specific CD8+ T cells using a variety of target cells including T cell lines, hybridomas and transfectants expressing distinct Vbeta determinants. Moreover, we will employ gene transfer techniques into relevant T cell lines to determine whether the expression of appropriate TCRbeta cDNA and/or Qa-1 cDNA renders cells susceptible to recognition by the Vbeta specific CD8+ T cells. Moreover, we will create a variety of recombinant TCRbeta cDNAs for gene transfer in order to define the regions and ultimately the Vbeta peptides which confer Vbeta specificity to target cells. Further aims of this grant include (l) further characterization of the Vbeta specific CD8+ T cells with respect to cell surface phenotype, TCR Vbeta repertoire, lymphokine secretion and the mechanisms that control their differentiation; (2) further study of the CD4+ inducer cells with respect to the ontogeny, physiology, kinetics and regulation of Qa-1 expression on distinct CD4+ T cell subsets; (3) defining the mechanisms of TCR presentation in the context of Qa-1 and (4) determining if TCR Vbeta specific cytolysis mediated by CD8+ T cells is a general biological phenomenon related to immunoregulation in vivo. In these latter studies we will adoptively transfer Vbeta specific CTL to SEB primed CD8-/- mice and determine if the normal regulation of CD4+, Vbeta8+ cells is restored and we will extend the analysis of Vbeta8 TCR to study the regulation of T cells expressing TCRs other than Vbeta8. Moreover, we will determine, by adoptive transfer of CD8+ Vbeta8 specific CTL, if CD4+ T cells activated by conventional peptide antigens, including peptides derived from myelin basic protein (MBP), are regulated by CD8+ T cells which recognize TCR Vbeta in association with Qa-1. In studies we will assay the effect of adoptive transfer on the clinical evolution of EAE.

由T细胞受体（TCR）介导的相互作用在不同的T中表达细胞子集可能在免疫调节中起作用。调查这个想法我们研究了超抗原诱导的TCR限制的调节回答。我们询问CD4+ VBETA8+ T细胞的体内调节是否 SEB注射后由CD8+ T细胞控制。我们发现在用单克隆抗CD8抗体处理CD8+细胞耗尽的小鼠或在CD8+ T细胞缺乏beta2 m - / - 小鼠中，延迟下调未观察到低于基线的CD4+ VBETA8+ T细胞。此外，遵循 SEB给药CD8+ T细胞出现，优先杀死激活的CD4+VBETA8+的亚群，但不是CD4+VBETA8- T细胞体外。这种TCR VBETA特异性细胞毒性取决于beta2 微型球蛋白，并被特定于QA-1的抗血清抑制，但不是 MHC I-A类的抗体。有趣的是，SEB激活增加了QA-1 表面表达并使T细胞容易受到裂解。这些数据表明免疫调节的特异性可能涉及CD8+ T细胞识别TCR VBETA决定因素和QA-1分子的识别抗原激活的CD4+ T细胞。在这笔赠款的第一个具体目标中，我们将使用使用VBETA特异性CD8+ T细胞的分子靶标多种靶细胞，包括T细胞系，杂交瘤和表达不同VBETA决定因素的转染物。而且，我们会的将基因转移技术采用相关的T细胞系来确定是否表达适当的TCRBETA cDNA和/或QA-1 cDNA 使细胞容易受到VBETA特异性CD8+ T的识别细胞。此外，我们将为基因转移以定义区域并最终vbeta 将VBETA特异性赋予靶细胞的肽。进一步的目标该赠款包括（l）进一步的VBETA特定CD8+的表征 T细胞相对于细胞表面表型，TCR VBETA曲目，淋巴动物的分泌和控制其的机制分化；（2）进一步研究CD4+诱导剂细胞在本体发育，生理学，动力学和质量质量表达的调节上不同的CD4+ T细胞子集；（3）定义TCR的机制在QA-1和（4）确定TCR VBETA的上下文中的演示由CD8+ T细胞介导的特异性胞得分是一种一般的生物学与体内免疫调节有关的现象。在这些后一个研究中，我们将通过过多地将VBETA特异性CTL转移到SEB Primed CD8 - / - 小鼠和确定CD4+的正常调节，VBETA8+细胞是否恢复，并我们将扩展对VBETA8 TCR的分析，以研究t的调节表达TCR的细胞以外的VBETA8。而且，我们将确定如果CD4+ T细胞激活CD8+ VBETA8特异性CTL的收养转移通过常规肽抗原，包括源自髓磷脂的肽碱性蛋白（MBP）受CD8+ T细胞的调节，这些细胞识别TCR VBETA与QA-1联合。在研究中，我们将分析 EAE临床演变的收养转移。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An integrated view of suppressor T cell subsets in immunoregulation.

DOI：
10.1172/jci23411
发表时间：
2004-11
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Hong Jiang;L. Chess
通讯作者：
Hong Jiang;L. Chess

The Qa-1 dependent CD8+ T cell mediated regulatory pathway.

DOI：
发表时间：
2005-06
期刊：
Cellular & molecular immunology
影响因子：
24.1
作者：
Hong Jiang
通讯作者：
Hong Jiang

An affinity/avidity model of peripheral T cell regulation.

外周 T 细胞调节的亲和力/亲合力模型。

DOI：
10.1172/jci23879
发表时间：
2005
期刊：
The Journal of clinical investigation.
影响因子：
0
作者：
Jiang,Hong;Wu,Yilun;Liang,Bitao;Zheng,Zongyu;Tang,Guomei;Kanellopoulos,Jean;Soloski,Mark;Winchester,Robert;Goldstein,Itamar;Chess,Leonard
通讯作者：
Chess,Leonard

An integrated model of immunoregulation mediated by regulatory T cell subsets.

由调节性 T 细胞亚群介导的免疫调节综合模型。