TCR affinity and negative regulation limit autoimmunity

Matthew A. Gronski, Jonathan M. Boulter, Dimitrios Moskofidis, 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

Research output: Contribution to journalArticle

121 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1234-1239
Number of pages6
JournalNature Medicine
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2004

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T-Cell Antigen Receptor
Autoimmunity
T-cells
Ligands
Autoimmune Diseases
Molecular Mimicry
T-Lymphocytes
Cytotoxic T-Lymphocytes
Pathogens
Virus Diseases
Viruses
Molecules
Incidence

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Gronski, M. A., Boulter, J. M., Moskofidis, D., Nguyen, L. T., Holmberg, K., Elford, A. R., ... Ohashi, P. S. (2004). TCR affinity and negative regulation limit autoimmunity. Nature Medicine, 10(11), 1234-1239. https://doi.org/10.1038/nm1114

TCR affinity and negative regulation limit autoimmunity. / Gronski, Matthew A.; Boulter, Jonathan M.; Moskofidis, Dimitrios; 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.

In: Nature Medicine, Vol. 10, No. 11, 01.11.2004, p. 1234-1239.

Research output: Contribution to journalArticle

Gronski, MA, Boulter, JM, Moskofidis, D, Nguyen, LT, Holmberg, K, Elford, AR, Deenick, EK, Kim, HO, Penninger, JM, Odermatt, B, Gallimore, A, Gascoigne, NRJ & Ohashi, PS 2004, 'TCR affinity and negative regulation limit autoimmunity', Nature Medicine, vol. 10, no. 11, pp. 1234-1239. https://doi.org/10.1038/nm1114
Gronski MA, Boulter JM, Moskofidis D, Nguyen LT, Holmberg K, Elford AR et al. TCR affinity and negative regulation limit autoimmunity. Nature Medicine. 2004 Nov 1;10(11):1234-1239. https://doi.org/10.1038/nm1114
Gronski, Matthew A. ; Boulter, Jonathan M. ; Moskofidis, Dimitrios ; 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. / TCR affinity and negative regulation limit autoimmunity. In: Nature Medicine. 2004 ; Vol. 10, No. 11. pp. 1234-1239.
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