Intrathymic selection: new insight into tumor immunology.

Central tolerance to self-antigens is formed in the thymus where deletion of clones with high affinity to "self" takes place. Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. During the last years, it has been shown that medullary thymic epithelial cells (mTECs) are the unique cell type expressing a diverse range of tissue-specific antigens. Promiscuous gene expression is a cell autonomous property of thymic epithelial cells and is maintained during the entire period of thymic T cell output. The array of promiscuously expressed self-antigens was random and included well-known targets for cancer immunotherapy, such as alpha-fetoprotein, P1A, tyrosinase, and gp100. Gene expression in normal tissues may result in tolerance of high-avidity cytotoxic T lymphocyte (CTL), leaving behind low-avidity CTL that cannot provide effective immunity against tumors expressing the relevant target antigens. Thus, it may be evident that tumor vaccines that targeted the tumor-associated antigens should be inefficient due to the loss of high-avidity T cell clones capable to be stimulated. Stauss with colleagues have described a strategy to circumvent immunological tolerance that can be used to generate high-avidity CTL against self-proteins, including human tumor-associated antigens. In this strategy, the allorestricted repertoire of T cells from allogenic donor is used as a source of T cell clones with high avidity to tumor antigens of recipient for adoptive immunotherapy. Then, the T cell receptor (TCR) genes isolated from antigen-specific T cells can be exploited as generic therapeutic molecules for antigen-specific immunotherapy.