Structural basis for self-recognition by autoimmune T-cell receptors

Immunol Rev. 2012 Nov;250(1):32-48. doi: 10.1111/imr.12002.


T-cell receptors (TCRs) recognize peptides presented by major histocompatibility complex molecules (pMHC) to discriminate between foreign and self-antigens. Whereas T-cell recognition of foreign peptides is essential for protection against microbial pathogens, recognition of self-peptides by T cells that have escaped negative selection in the thymus can lead to autoimmune disease. Structural studies of autoimmune TCR-pMHC complexes have provided insights into the mechanisms underlying self-recognition and escape from thymic deletion. Two broad categories of self-reactive TCRs can be clearly distinguished: (i) TCRs with altered binding topologies to self-pMHC and (ii) TCRs that bind self-pMHC in the canonical diagonal orientation, but where there are structural defects or suboptimal anchors in the self-ligand. For both categories, however, the overall stability of the autoimmune TCR-pMHC complex is markedly reduced compared to anti-microbial complexes, allowing the autoreactive T cells to evade negative selection, yet retain the ability to be activated by self-antigens in target organs. Additionally, the structures provide insights into TCR cross-reactivity, which can contribute to autoimmunity by increasing the likelihood of self-pMHC recognition. Efforts are now underway to understand the impact of structural alterations in autoimmune TCR-pMHC complexes on higher order assemblies involved in TCR signaling, as well as on immunological synapse formation.

Publication types

  • Review

MeSH terms

  • Animals
  • Autoantigens / chemistry*
  • Autoantigens / immunology
  • Autoantigens / metabolism
  • Autoimmunity*
  • Binding Sites
  • Cross Reactions
  • Humans
  • Major Histocompatibility Complex / immunology*
  • Mice
  • Models, Molecular
  • Peptides / chemistry*
  • Peptides / immunology
  • Peptides / metabolism
  • Protein Binding
  • Protein Conformation
  • Receptors, Antigen, T-Cell / chemistry*
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • T-Cell Antigen Receptor Specificity
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism


  • Autoantigens
  • Peptides
  • Receptors, Antigen, T-Cell