CD4+ T cell subset function in antitumor immune response

描述(申请人提供)：在表达野生型T细胞受体(TCR)的小鼠中，肿瘤抗原特异性T细胞的频率很低，这阻碍了对肿瘤细胞免疫反应早期事件的研究。尽管利用转基因小鼠或过继转移的针对肿瘤抗原的转基因T细胞有助于克服这些困难，但基于单克隆转基因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更多了解，TCR对抗原的亲和力、与抗原的初始接触部位、抗原提呈细胞的性质和T细胞的功能状态可能决定单个T细胞的激活结果，并最终决定免疫反应的过程。特别是，CD4+T淋巴细胞可以分化为效应性辅助细胞，但也可能成为无能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，我们建立了一个新的实验小鼠模型，该模型具有限制性的但多克隆的TCR谱系，偏向于识别已知的抗原。在这个模型系统中，大多数CD4+T细胞表达200-400种不同的TCR，这使得在T细胞个体发育或对抗原的反应中跟踪不同亚群中具有特定特异性的细胞的频率成为可能。这一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谱系，以揭示抗原特异性T细胞的克隆性扩增和募集。由CD4+T细胞亚群表达的TCR亲和力的范围将被表征，并与T细胞在肿瘤组织中被招募和保留的能力相关。我们还将调查肿瘤组织中具有效应和调节功能的T细胞的来源，并试图在健康小鼠的T细胞群中确定这些细胞的前体。

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.