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Letter
Nature Medicine 10, 1234 - 1239 (2004)
Published online: 3 October 2004 | doi:10.1038/nm1114
TCR affinity and negative regulation limit autoimmunity
Matthew A Gronski1, Jonathan M Boulter2, Demetrius Moskophidis3, Linh T Nguyen1, Kaisa Holmberg4, Alisha R Elford1, Elissa K Deenick1, Hee O Kim4, Josef M Penninger5, Bernhard Odermatt6, Awen Gallimore2, Nicholas R J Gascoigne4 & Pamela S Ohashi1
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 ligands1, 2, 3. 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-b4, 5, 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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