title: Structural basis for self-recognition by autoimmune T-cell receptors.
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.
authors.affiliation: Department of Antibody Engineering, Genentech, South San Francisco, CA, USA.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Yin
authors.forename: Yili
authors.initials: Y
authors.lastname: Li
authors.forename: Roy A
authors.initials: RA
authors.lastname: Mariuzza
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D001665:Binding Sites; D003429:Cross Reactions; D006801:Humans; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D001324:Autoantigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell