Autoimmune diseases are caused by self-reactive lymphocytes that have escaped deletion. Here we have determined the structure of the trimolecular complex for a T cell receptor (TCR) from a patient with multiple sclerosis that causes autoimmunity in transgenic mice. The structure showed a TCR topology notably different from that of antimicrobial TCRs. Rather than being centered on the peptide-major histocompatibility complex, this TCR contacted only the N-terminal peptide segment and made asymmetrical interactions with the major histocompatibility complex helices. The interaction was dominated by the hypervariable complementarity-determining region 3 loops, indicating that unconventional topologies are possible because of the unique complementaritydetermining region 3 sequences created during rearrangement. This topology reduces the interaction surface with peptide and alters the geometry for CD4 association. We propose that unusual TCR-binding properties can permit autoreactive T cells to escape deletion.Autoimmune diseases are caused by aberrant responses of self-reactive T cells and B cells, which are present in every person despite elaborate mechanisms for eliminating or silencing such cells 1 . T cell receptors (TCRs) recognize peptide fragments bound to major histocompatibility complex (MHC) glycoproteins, and rearrangement of TCR gene segments during T cell development in the thymus produces a highly diverse repertoire 2 . This enormous diversity ensures that almost any pathogen-derived peptide can be recognized during an infection, but also creates an autoimmunity hazard. Immature thymocytes undergo selection based on recognition of self peptide-MHC complexes, and the outcome represents a delicate balance: survival of thymocytes depends on weak interactions with self peptide-MHC complexes (positive selection), whereas apoptosis is induced by stronger TCR signals (negative selection) [3][4][5] . Almost all 'tissue-specific' antigens are presented to immature T cells in the thymus by a specialized subpopulation of medullary epithelial cells 6 . 'Promiscuous' antigen expression by these cells is in part regulated by the transcription factor Aire, and deficiency in this protein results in autoimmunity against multiple organs in mice and humans 7,8 . © 2005 Nature Publishing GroupCorrespondence should be addressed to K.W.W. (kai_wucherpfennig@dfci.harvard.edu). Supplementary information is available on the Nature Immunology website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. Why do some autoreactive T cells escape negative selection? For some antigens, failure of negative selection has been attributed to an unusually low affinity of the self peptide for the MHC 9 or to alternative splice forms in the thymus that do not contain the T cell epitope 10 . However, these mechanisms do not account for most autoimmune T cell epitopes. They also do not explain the presence of T cells that recognize a peptide consisting of myelin basic protein (MBP) residues...

DM catalyzes the exchange of peptides bound to Class II major histocompatibility complex (MHC) molecules. Because the dissociation and association components of the overall reaction are difficult to separate, a detailed mechanism of DM catalysis has long resisted elucidation. UV irradiation of DR molecules loaded with a photocleavable peptide (caged Class II MHC molecules) enabled synchronous and verifiable evacuation of the peptide-binding groove and tracking of early binding events in real time by fluorescence polarization. Empty DR molecules generated by photocleavage rapidly bound peptide but quickly resolved into species with substantially slower binding kinetics. DM formed a complex with empty DR molecules that bound peptide with even faster kinetics than empty DR molecules just having lost their peptide cargo. Mathematical models demonstrate that the peptide association rate of DR molecules is substantially higher in the presence of DM. We therefore unequivocally establish that DM contributes directly to peptide association through formation of a peptide-loading complex between DM and empty Class II MHC. This complex rapidly acquires a peptide analogous to the MHC class I peptide-loading complex.Major histocompatibility complex (MHC) 5 molecules are cell surface proteins that present peptides to antigen-specific receptors on T cells. The Class II MHC products are specialized in sampling endosomal compartments to acquire these peptides. Delivery of newly synthesized and assembled Class II MHC proteins to endo-lysosomal compartments is assured by means of the transient association of the MHC ␣␤ heterodimer with the invariant chain, a protein endowed with both chaperone function and an address code (1, 2). In endosomal compartments, the invariant chain is destroyed, yielding a Class II MHC product occupied with an invariant chain-derived remnant, the CLIP peptide (3-5). The HLA-DM (DM) molecule, itself incapable of binding peptide, facilitates replacement of CLIP with antigenic peptides (6 -10). The action of DM is not limited to the Class II MHC/CLIP complex and extends to Class II MHCpeptide complexes more generally. Such editing by DM favors presentation to CD4 T cells of those peptides that are most resistant to peptide displacement by DM (9,(11)(12)(13)(14)(15)(16)(17).DM is a membrane-anchored heterodimer that belongs to the extended family of proteins with a MHC fold but lacks a functional peptide-binding groove (18,19). Mutagenesis experiments identified lateral surfaces on DM and DR molecules that are involved in the interaction between the two proteins. On the DR side, these mutations span the entire length of the ectodomain and are localized to the ␣1 and ␤2 domains (20). On the DM side, an extended interaction surface has been mapped that also spans the entire length of the ectodomain (21). These data support a model in which lateral interactions between DM and DR molecules induce a conformational change that destabilizes the DR-bound peptide. It has been proposed that DM disrupts one or severa...

Superantigens (SAGs) bind simultaneously to major histocompatibility complex (MHC) and T-cell receptor (TCR) molecules, resulting in the massive release of inflammatory cytokines that can lead to toxic shock syndrome (TSS) and death. A major causative agent of TSS is toxic shock syndrome toxin-1 (TSST-1), which is unique relative to other bacterial SAGs owing to its structural divergence and its stringent TCR specificity. Here, we report the crystal structure of TSST-1 in complex with an affinity-matured variant of its wild-type TCR ligand, human T-cell receptor b chain variable domain 2.1. From this structure and a model of the wild-type complex, we show that TSST-1 engages TCR ligands in a markedly different way than do other SAGs. We provide a structural basis for the high TCR specificity of TSST-1 and present a model of the TSST-1-dependent MHC-SAG-TCR T-cell signaling complex that is structurally and energetically unique relative to those formed by other SAGs. Our data also suggest that protein plasticity plays an exceptionally significant role in this affinity maturation process that results in more than a 3000-fold increase in affinity.