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- Title
TCR affinity and negative regulation limit autoimmunity.
- 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
- 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.
- Publication
Nature medicine, 2004, Vol 10, Issue 11, p1234
- ISSN
1078-8956
- Publication type
Journal Article
- DOI
10.1038/nm1114