Autoaggression and tumor rejection: it takes more than self-specific T-cell activation.
Establishment of self-tolerance prevents autoaggression against organ-specific self-antigens. This beneficial effect, however, may in turn be responsible for tumor immune evasion. Thus, dissecting the mechanisms leading to the 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-specific T-cell activation. Here, we discuss two transgenic mouse models which demonstrate that both autoaggression and tumor rejection require more than activated, self-reactive T cells. TCR transgenic mice, which are tolerant to a liver-specific MHC class I antigen, Kb, can be activated to reject Kb-positive grafts, but fail to attack Kb-expressing liver. However, autoaggression occurs when activated T cells are combined with "conditioning" of the target organ by irradiation or infection with a liver-specific pathogen. Similarly, in a mouse model of islet cell carcinoma, neither co-stimulatory tumor cells nor highly activated antitumor lymphocytes provoke an effective immune response against the tumor. Instead, a combination of activated lymphocytes and irradiation is required for lymphocyte infiltration into solid tumors. Both model systems provide evidence that although activated antigen-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 microenvironment is a critical parameter in determining the effectiveness of an anti-self immune response.
Ganss
R
R
Division of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.
Limmer
A
A
Sacher
T
T
Arnold
B
B
Hämmerling
G J
GJ
D007516:Adenoma, Islet Cell / Q000276:immunology; D000818:Animals; D015551:Autoimmunity; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D006084:Graft Rejection; D006801:Humans; D007167:Immunotherapy; D008099:Liver / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D011948:Receptors, Antigen, T-Cell