Unconventional topology of self peptide–major histocompatibility complex binding by a human autoimmune T cell receptor

Abstract

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...

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

“…30 These hydrophobic residues may act as TCR contact points, implying a rather restricted set of TCR-complementary determinant region recognition elements, as well as a non-canonical orientation for the TCRs, as described in multiple sclerosis. 47,48 By contrast, the two HLA-DQ6-restricted 13-mer epitopes in the insulin B chain have several hydrophilic residues, rendering these peptides less likely to act as contact points of hydrophobic complementary determinant regions on pathogenic TCRs.…”

Lysosomal Cysteine and Aspartic Proteases Are Heterogeneously Expressed and Act Redundantly to Initiate Human Invariant Chain Degradation

“…We tested the ability of AEP-inhibited B cells to activate a MBPreactive T cell clone isolated from the periphery of a patient with MS (24). This MBP-restricted clone binds in an unconventional manner to the N-terminal segment of the 85-99 peptide and is unresponsive to HPLC-purified MBP in the absence of intracellular processing (41,42). We found that inactivation of AEP did not result in significant disruption of MBP peptide 85-99 presentation by these cells (Fig.…”

Central tolerance: Essential for preventing autoimmune disease?

“…Conceivably, this could also disturb the balance of positive selection and Treg generation. Of considerable interest is the notion that several class II MHC-presented epitopes that are recognized by disease causing T-cell clones are presented in an MHC binding register that is unusual because it minimizes binding to class II MHC molecules that themselves present genetic factors contributing to disease [49,50]. This holds true for epitopes recognized by T cells causing experimental allergic encephalomyelitis (EAE), or multiple sclerosis (MS), as well as epitopes recognized by type 1 diabetes causing T-cell clones specific for insulin [51].…”