TCR affinity and negative regulation limit autoimmunity
Author: ["Matthew A Gronski","Jonathan M Boulter","Demetrius Moskophidis","Linh T Nguyen","Kaisa Holmberg","Alisha R Elford","Elissa K Deenick","Hee O Kim","Josef M Penninger","Bernhard Odermatt","Awen Gallimore","Nicholas R J Gascoigne","Pamela S Ohashi"]
Publication: Nature Medicine
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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 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.
Cite this article
Gronski, M., Boulter, J., Moskophidis, D. et al. TCR affinity and negative regulation limit autoimmunity. Nat Med 10, 1234–1239 (2004). https://doi.org/10.1038/nm1114
