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. ? ?
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