T cell tolerance induced by cross-reactive TCR ligands can be broken by superagonist resulting in anti-inflammatory T cell cytokine production

J Immunol. 2005 Aug 1;175(3):1491-7. doi: 10.4049/jimmunol.175.3.1491.


Cross-reactive activation of potentially autoreactive T cells by high-affinity nonself ligands may be important in breaking self-tolerance in autoimmunity. In a mouse transgenic for a cross-reactive TCR, we have previously shown that a hyper-stimulating altered peptide ligand, L144, induced unresponsiveness to the self peptide, proteolipid protein 139-151. In this study, we demonstrate that a superagonist ligand can break T cell tolerance induced by the lower affinity cognate Ag. T cells tolerant to the cognate ligand, Q144, responded to superagonist, L144, by proliferation and the production of mainly IL-4 and IL-10 in vitro. In contrast, T cells that were tolerized to the superagonist were unable to respond to any peptide that cross-reacted with the transgenic TCR. Low-dose immunization with the superagonist L144 was able to break tolerance to the cognate ligand in vivo and resulted in a blunted proliferative response with production of Th2 cytokines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Clonal Anergy* / genetics
  • Clonal Anergy* / immunology
  • Cytokines / antagonists & inhibitors
  • Cytokines / biosynthesis*
  • Dose-Response Relationship, Immunologic
  • Female
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism*
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / biosynthesis
  • Interleukin-2 / antagonists & inhibitors
  • Interleukin-2 / biosynthesis
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / immunology*
  • Peptide Fragments / metabolism
  • Receptors, Antigen, T-Cell / agonists*
  • Receptors, Antigen, T-Cell / biosynthesis
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / transplantation


  • Cytokines
  • Inflammation Mediators
  • Interleukin-2
  • Ligands
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • Interferon-gamma