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Tcr affinity and negative regulation limit autoimmunity

Academic Article
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Overview

authors

  • Gronski, M. A.
  • Boulter, J. M.
  • Moskophidis, D.
  • Nguyen, L. T.
  • Holmberg, K.
  • Elford, A. R.
  • Deenick, E. K.
  • Kim, H. O.
  • Penninger, J. M.
  • Odermatt, B.
  • Gallimore, A.
  • Gascoigne, Nicholas
  • Ohashi, P. S.

publication date

  • November 2004

journal

  • Nature Medicine  Journal

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.

subject areas

  • Animals
  • Autoimmunity
  • Cell Proliferation
  • Chromium Radioisotopes
  • Diabetes Mellitus, Experimental
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Ligands
  • Lymphocytic choriomeningitis virus
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Immunological
  • Molecular Mimicry
  • Receptors, Antigen, T-Cell
  • T-Lymphocytes, Cytotoxic
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Identity

International Standard Serial Number (ISSN)

  • 1078-8956

Digital Object Identifier (DOI)

  • 10.1038/nm1114

PubMed ID

  • 15467726
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Additional Document Info

start page

  • 1234

end page

  • 1239

volume

  • 10

issue

  • 11

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