TCR affinity and negative regulation limit autoimmunity |
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Authors: | Gronski Matthew A Boulter Jonathan M Moskophidis Demetrius Nguyen Linh T Holmberg Kaisa Elford Alisha R Deenick Elissa K Kim Hee O Penninger Josef M Odermatt Bernhard Gallimore Awen Gascoigne Nicholas R J Ohashi Pamela S |
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Institution: | Institute for Breast Cancer Research, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada. |
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Abstract: | Autoimmune diseases are often mediated by self-reactive T cells, which must be activated to cause immunopathology. One mechanism, known as molecular mimicry, proposes that self-reactive T cells may be activated by pathogens expressing crossreactive ligands. Here we have developed a model to investigate how the affinity of the T-cell receptor (TCR) for the activating agent influences autoimmunity. Our model shows that an approximately fivefold difference in the TCR affinity for the activating ligand results in a 50% reduction in the incidence of autoimmunity. A reduction in TCR-ligand affinity to approximately 20 times lower than normal does not induce autoimmunity despite the unexpected induction of cytotoxic T lymphocytes (CTLs) and insulitis. Furthermore, in the absence of a key negative regulatory molecule, Cbl-b, 100% of mice develop autoimmunity upon infection with viruses encoding the lower-affinity ligand. Therefore, autoimmune disease is sensitive both to the affinity of the activating ligand and to normal mechanisms that negatively regulate the immune response. |
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