CD4+ T cell subset function in antitumor immune response

CD4 T 细胞亚群在抗肿瘤免疫反应中发挥作用

基本信息

批准号：
7564715
负责人：
Piotr J. Kraj
金额：
$ 20.41万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-16 至 2011-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The low frequency of tumor antigen-specific T cells in mice expressing a wild-type repertoire of T cell receptors (TCRs) has thwarted attempts to investigate early events in the immune response to tumor cells. Although utilization of transgenic mice or adoptively transferred transgenic T cells specific for tumor antigens has helped to overcome these difficulties, experimental systems based on the use of monoclonal transgenic T cells do not reflect the polyclonal nature of the immune response. As more is learned about the initiation and regulation of response to antigens, it becomes apparent that the affinity of the TCR for antigen, the site of initial contact with antigen, the nature of the antigen presenting cell, and the functional status of a T cell may determine the outcome of activation of individual T cells and, ultimately, the course of the immune response. In particular, a CD4+ T lymphocyte may differentiate into an effector helper cell, but may also become anergic or a regulatory T cell that suppresses the antigen response of other cells. To characterize early events in the activation of tumor-specific T cells in vivo, we have produced a new experimental mouse model with a restricted, but polyclonal, TCR repertoire biased to recognize a known antigen. In this model system, the majority of CD4+ T cells express one of 200-400 different TCRs, which makes it possible to track the frequency of cells with a particular specificity in different subpopulations during T cell ontogeny or response to antigen. This new experimental model will be used to investigate the initial stages of the anti-tumor immune response to reveal how tolerance to tumor cells is established. We will examine TCR repertoire expressed by functional T cell subsets to reveal clonal expansion and recruitment of antigen-specific T cells. The range of TCR affinities expressed by CD4+ T cell subsets will be characterized and correlated with the capacity of T cells to be recruited and retained, in tumor tissue. We will also investigate what is the origin of T cells with effector and regulatory function-in tumor tissue and try to identify precursors of these cells in the T cell population of healthy mice.

描述（由申请人提供）：表达野生型 T 细胞受体 (TCR) 的小鼠中肿瘤抗原特异性 T 细胞的低频率阻碍了研究肿瘤细胞免疫反应早期事件的尝试。尽管利用转基因小鼠或过继转移的肿瘤抗原特异性转基因T细胞有助于克服这些困难，但基于使用单克隆转基因T细胞的实验系统并不能反映免疫反应的多克隆性质。随着对抗原反应的启动和调节的了解越来越多，TCR 对抗原的亲和力、与抗原初始接触的位点、抗原呈递细胞的性质以及 T 细胞的功能状态之间的关系变得越来越明显。可能决定单个 T 细胞激活的结果，并最终决定免疫反应的过程。特别是，CD4+ T 淋巴细胞可能分化为效应辅助细胞，但也可能变成无能细胞或抑制其他细胞抗原反应的调节性 T 细胞。为了表征体内肿瘤特异性 T 细胞激活的早期事件，我们制作了一种新的实验小鼠模型，该模型具有有限但多克隆的 TCR 库，偏向于识别已知抗原。在此模型系统中，大多数 CD4+ T 细胞表达 200-400 种不同 TCR 之一，这使得在 T 细胞个体发育或对抗原反应期间追踪不同亚群中具有特定特异性的细胞频率成为可能。这个新的实验模型将用于研究抗肿瘤免疫反应的初始阶段，以揭示对肿瘤细胞的耐受性是如何建立的。我们将检查功能性 T 细胞亚群表达的 TCR 库，以揭示抗原特异性 T 细胞的克隆扩增和招募。 CD4+ T 细胞亚群表达的 TCR 亲和力范围将被表征，并与肿瘤组织中 T 细胞招募和保留的能力相关联。我们还将研究肿瘤组织中具有效应和调节功能的 T 细胞的起源，并尝试在健康小鼠的 T 细胞群中鉴定这些细胞的前体。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intratumoral convergence of the TCR repertoires of effector and Foxp3+ CD4+ T cells.

效应 T 细胞和 Foxp3 CD4 T 细胞的 TCR 库在肿瘤内融合。

DOI：
发表时间：
2010-10-26
期刊：
影响因子：
3.7
作者：
Kuczma, Michal;Kopij, Magdalena;Pawlikowska, Iwona;Wang, Cong;Rempala, Grzegorz A;Kraj, Piotr
通讯作者：
Kraj, Piotr

Connexin 43 signaling enhances the generation of Foxp3+ regulatory T cells.

Connexin 43 信号传导可增强 Foxp3 调节性 T 细胞的生成。

DOI：
发表时间：
2011-07-01
期刊：
影响因子：
0
作者：
Kuczma, Michal;Lee, Jeffrey R;Kraj, Piotr
通讯作者：
Kraj, Piotr

TCR repertoire and Foxp3 expression define functionally distinct subsets of CD4+ regulatory T cells.

TCR 库和 Foxp3 表达定义了功能上不同的 CD4 调节性 T 细胞亚群。

DOI：
发表时间：
2009-09-01
期刊：
影响因子：
0
作者：
Kuczma, Michal;Pawlikowska, Iwona;Kopij, Magdalena;Podolsky, Robert;Rempala, Grzegorz A.;Kraj, Piotr
通讯作者：
Kraj, Piotr