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

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleStructural basis for self-recognition by autoimmune T-cell receptors.
Publication TypeJournal Article
Year of Publication2012
AuthorsYin, Y, Li, Y, Mariuzza, RA
JournalImmunol Rev
Volume250
Issue1
Pagination32-48
Date Published2012 Nov
ISSN1600-065X
KeywordsAnimals, Autoantigens, Autoimmunity, Binding Sites, Cross Reactions, Humans, Major Histocompatibility Complex, Mice, Models, Molecular, Peptides, Protein Binding, Protein Conformation, Receptors, Antigen, T-Cell, T-Cell Antigen Receptor Specificity, T-Lymphocytes
Abstract

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.

DOI10.1111/imr.12002
Alternate JournalImmunol. Rev.
PubMed ID23046121