CD4+ T cell subset function in antitumor immune response

描述（由申请方提供）：表达野生型T细胞受体（TCR）库的小鼠中肿瘤抗原特异性T细胞的频率较低，阻碍了研究对肿瘤细胞免疫应答早期事件的尝试。虽然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，实验系统的基础上使用的单克隆转基因T细胞不反映多克隆的免疫反应的性质。随着对抗原应答的起始和调节了解的更多，变得明显的是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和T细胞的功能状态可以决定单个T细胞活化的结果，并最终决定免疫应答的过程。特别是，CD 4 + T淋巴细胞可以分化成效应辅助细胞，但也可以成为无反应性或抑制其他细胞的抗原应答的调节性T细胞。为了表征体内肿瘤特异性T细胞活化的早期事件，我们已经产生了一种新的实验小鼠模型，该模型具有有限的但多克隆的TCR库，其偏向于识别已知抗原。在该模型系统中，大多数CD 4 + T细胞表达200-400种不同TCR中的一种，这使得有可能在T细胞个体发育或对抗原的应答期间追踪不同亚群中具有特定特异性的细胞的频率。这种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。我们将检查由功能性T细胞亚群表达的TCR库，以揭示抗原特异性T细胞的克隆扩增和募集。由CD 4 + T细胞亚群表达的TCR亲和力的范围将被表征并与T细胞在肿瘤组织中募集和保留的能力相关。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，并试图在健康小鼠的T细胞群中识别这些细胞的前体。

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.