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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7564715
• 关键词: Affinity; Antigen-Presenting Cells; Antigens; Biological Models; CD4 Positive T Lymphocytes; Cells; Clonal Expansion; Cross Presentation; Development; Environment; Event; Experimental Models; Frequencies; Helper-Inducer T-Lymphocyte; Immune response; Immunosuppression; Individual; Learning; Lesion; Lymphoid; Malignant Neoplasms; Mus; Nature; Organ; Outcome; Pattern; Peripheral; Phenotype; Population; Recruitment Activity; Regulation; Role; Site; Specificity; Staging; Surface Antigens; System; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Thymus Gland; Time; Transgenic Mice; Transgenic Organisms; Tumor Antigens; Tumor Tissue; base; cytokine; functional status; in vivo; lymph nodes; mouse model; neoplastic cell; precursor cell; receptor; response; tumor

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T细胞受体野生型曲目（TCR）的小鼠中肿瘤抗原特异性T细胞的低频（TCRS）阻碍了研究对肿瘤细胞免疫反应的早期事件的尝试。尽管对转基因小鼠的利用或针对肿瘤抗原特异的转基因T细胞的利用有助于克服这些困难，但基于单克隆转基因T细胞使用的实验系统并不能反映免疫反应的多克隆性质。随着有关对抗原反应的启动和调节的更多信息，很明显，TCR对抗原的亲和力，与抗原的初始接触部位，抗原呈现细胞的性质以及T细胞的功能状态可以确定单个T细胞激活的结果以及最终的免疫反应疗程。特别是，CD4+ T淋巴细胞可能会分化为效应辅助细胞，但也可能成为抑制其他细胞抗原反应的厌食症或调节性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，具有受限制但多克隆的TCR曲目有偏见以识别已知抗原。在此模型系统中，大多数CD4+ T细胞表达了200-400种不同的TCR之一，这使得在T细胞个体发育或对抗原反应期间在不同亚群中具有特定特异性的细胞频率可以跟踪细胞的频率。该新的实验模型将用于研究抗肿瘤免疫反应的初始阶段，以揭示如何建立对肿瘤细胞的耐受性。我们将研究由功能性T细胞子集表达的TCR库，以揭示克隆扩张和募集抗原特异性T细胞。 CD4+ T细胞子集表达的TCR亲和力的范围将被表征并与在肿瘤组织中募集和保留的T细胞的能力相关。我们还将研究具有效应和调节功能的T细胞的起源，并试图鉴定健康小鼠T细胞群中这些细胞的前体。

项目成果

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

• DOI: 10.1371/journal.pone.0013623
• 发表时间: 2010-10-26
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kuczma M;Kopij M;Pawlikowska I;Wang CY;Rempala GA;Kraj P
• 通讯作者: Kraj P

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

• DOI: 10.4049/jimmunol.1003785
• 发表时间: 2011-07-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kuczma M;Lee JR;Kraj P
• 通讯作者: Kraj P

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: 10.4049/jimmunol.0900514
• 发表时间: 2009-09-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Kuczma, Michal;Pawlikowska, Iwona;Kopij, Magdalena;Podolsky, Robert;Rempala, Grzegorz A.;Kraj, Piotr
• 通讯作者: Kraj, Piotr