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

Summary T‐cell receptors ( TCR s) recognize peptides presented by major histocompatibility complex molecules (p MHC ) 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 –p MHC 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) TCR s with altered binding topologies to self‐p MHC and (ii) TCR s that bind self‐p MHC 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 –p MHC 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‐p MHC recognition. Efforts are now underway to understand the impact of structural alterations in autoimmune TCR –p MHC complexes on higher order assemblies involved in TCR signaling, as well as on immunological synapse formation.