Antigen analogs as tools to study T-cell activation function and activation.
Herein we review data relating to the molecular mechanism of T-cell receptor antagonists, their effect on thymic education, the occurrence of naturally occurring antigen analogs, and the therapeutic potential of the TCR antagonist approach. Our data suggest that MHC bound antigen analogs which antagonize the mature T-cell response, bind the T-cell receptor below a crucial affinity threshold required to stimulate the early biochemical events necessary for activation, such as phosphatidylinositol metabolism and the Ca2+ influx. The same peptides do not inhibit the formation of APC/T-cell complexes, suggesting interference with more complex equilibria such as receptor oligomerization and co-receptor interaction. Our laboratory and others have also begun to investigate how these antigen analogs may affect the processes involved in thymic education. Non-stimulatory antagonist peptides can elicit deletion of CD4+/CD8+ thymocytes suggesting a lower affinity requirement for negative selection than for activation. These data also demonstrate that these antigen analogs can, indeed, act upon immature T cells. We have also reviewed evidence that antagonists may, in fact, occur in nature. Recent data suggest that viral mutations resulting in altered immunodominant epitopes may produce antagonist determinants potentially involved in immunosuppression and viral persistence. Finally, we discuss the therapeutic potential of antigen analogs and TCR antagonism in autoimmune disease and allergy.
Sette
A
A
Cytel Corporation, San Diego, CA 92112, USA.
Alexander
J
J
Snoke
K
K
Grey
H M
HM
D000818:Animals; D000941:Antigens / Q000737:chemistry*; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology
D000941:Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell