Failure to induce organ-specific autoimmunity by breaking of tolerance: importance of the microenvironment.
Peripheral tolerance is considered to be a safeguard against autoimmunity. Using a TCR-transgenic mouse system displaying peripheral tolerance against a liver-specific MHC class I Kb antigen, we investigated whether the breaking of tolerance would result in autoimmunity. Reversal of tolerance was achieved by simultaneous challenge with cells expressing the Kb autoantigen and IL-2. Tolerance could not be broken with IL-2 alone or when Kb- and IL-2-expressing cells were applied to different sites of the mice. However, despite the presence of activated autoreactive T cells that were able to reject Kb-positive grafts no autoaggression against the Kb-positive liver was observed. These results indicate that breaking of tolerance per se is not sufficient to cause liver-specific autoimmunity. However, when in addition to breaking tolerance the mice were infected with a liver-specific pathogen, autoaggression occurred. Thus, in this system at least two independent steps seem to be required for organ-specific autoimmunity: reversal of peripheral tolerance resulting in functional activation of autoreactive T cells and conditioning of the liver microenvironment which enables the activated T cells to cause tissue damage.
Division of Molecular Immunology, German Cancer Research Center, Heidelberg.
A
A
Limmer
T
T
Sacher
J
J
Alferink
M
M
Kretschmar
G
G
Schönrich
T
T
Nichterlein
B
B
Arnold
G J
GJ
Hämmerling
D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage / Q000235:genetics; D015551:Autoimmunity; D006084:Graft Rejection / Q000276:immunology; D006183:H-2 Antigens / Q000008:administration & dosage / Q000235:genetics; D006520:Hepatitis, Animal / Q000276:immunology / Q000473:pathology; D007376:Interleukin-2 / Q000494:pharmacology; D008088:Listeriosis / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology; D008213:Lymphocyte Activation; D012515:Mast-Cell Sarcoma / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology
D001324:Autoantigens; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D007376:Interleukin-2