Autoaggression and tumor rejection: it takes more than self-specific T-cell activation

Establishment of self-tolerance prevents autoaggression against organ-speci fic self-antigens. This beneficial effect, however, may in turn be responsi ble for tumor immune evasion. Thus, dissecting the mechanisms leading to th e breakdown of self-tolerance in autoimmune diseases might provide insights for successful antitumor immune therapies. In a variety of animal models, organ- or tumor-specific immunity has been described, focusing on antigen-s pecific T-cell activation. Here, we discuss two transgenic mouse models whi ch demonstrate that both autoaggression and tumor rejection require more th an activated, self-reactive T cells. TCR transgenic mice, which are toleran t to a liver-specific MHC crass I antigen, K-b, can be activated to reject K-b-positive grafts, but fail to attack K-b-expressing liver. However, auto aggression occurs when activated T cells are combined with "conditioning" o f the target organ by irradiation or infection with a liver-specific pathog en. Similarly, in a mouse model of islet cell carcinoma, neither co-stimula tory tumor cells nor highly activated antitumor lymphocytes provoke an effe ctive immune response against the tumor. Instead, a combination of activate d lymphocytes and irradiation is required for lymphocyte infiltration into solid tumors. Both model systems provide evidence that although activated a ntigen-specific lymphocytes are a prerequisite for autoaggression, effector cell extravasation and appropriate interaction with the target organ/tumor are equally important. Thus, we propose that the organ/tumor microenvironm ent is a critical parameter in determining the effectiveness of an anti-sel f immune response.