Tertiary complex of an MS-related TCR (Ob)with an antigenic peptide of bacterial origin presented ...
The immune system is a near perfect fighting machine that can recognise millions of pathogenic life forms. The foot soldiers in this battle are T lymphocytes which will either directly attack infected cells or signal the presence of invaders to antibody producing cells. They recognise infection via specialised T cell receptors (TCRs) which bind antigenic peptides presented by MHC molecules on the surface of infected cells. Through an intricate series of DNA recombination events there is quite literally a T cell receptor for every possible pathogen a human being might encounter. However this amazing arsenal of receptors is sustained at a potential cost because although lymphocytes are trained to ignore healthy an antigen sharing significant similarity to a self component can potentially kick-start an immune response that will ultimately target healthy tissue as well leading to autoimmune pathologies such as multiple sclerosis.
To date our knowledge of the molecular aspects of autoimmunity is limited hence and we are currently working on a number of autoimmunity-related TCRs. Multiple sclerosis in specific, is an incurable chronic inflammatory disease of the central nervous system associated with MHC class II molecules, DR2a and DR2b. A highly cross-reactive MS patient-derived TCR (Hy) recognises a self peptide presented by DR2b as well as several viral peptides presented by DR2a. Such cross-reactivity suggests that viral infections could trigger MS by stimulating self-reactive cells. To study the underlying mechanism of this process we aim to decipher the atomic structure of Hy in complex with antigenic foreign- and self-peptides presented by their respective MHCs. We will use the resulting atomic structures to compose a model system for analysis of structural mimicry features implicated in autoimmunity. It is our hope that understanding the pathogenesis of autoimmunity in atomic detail will ultimately lead us to suggest possible treatments.
Our laboratory specialises in protein X-ray crystallography which enables us to look at the 3-D structure of autoimmunity-specific biomolecules and relate their particular features to their pathogenic potential. Students will have to opportunity to gain experience in molecular cloning, recombinant protein production in both bacterial and mammalian expression systems, purification of proteins, crystallisation of protein complexes using state-of-the-art crystallisation facilities and structure determination and analysis.
Our work is closely synergistic with the clinical group of L. Fugger at the IMM allowing for an interdisciplinary approach to our investigations
Protein Science & Structural Biology
Project reference number: 113
| Name | Department | Institution | Country | |
|---|---|---|---|---|
| Dr Maria Harkiolaki | Structural Biology | Oxford University | UK | maria@strubi.ox.ac.uk |
2005. Immunology of multiple sclerosis. Annu. Rev. Immunol., 23 pp. 683-747. Read abstract | Read more
Multiple sclerosis (MS) develops in young adults with a complex predisposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype are a crucial events in the initial steps, and these cells are probably also important players in the long-term evolution of the disease. Damage of the target tissue, the central nervous system, is, however, most likely mediated by other components of the immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells. Perturbations in immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NK cells, and others may in part be responsible for the relapsing-remitting or chronic progressive nature of the disease. However, an important paradigmatic shift in the study of MS has occurred in the past decade. It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future. Hide abstract
1999. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nat. Genet., 23 (3), pp. 343-7. Read abstract | Read more
Multiple sclerosis (MS) is a complex chronic neurologic disease with a suspected autoimmune pathogenesis. Although there is evidence that the development of MS is determined by both environmental influences and genes, these factors are largely undefined, except for major histocompatibility (MHC) genes. Linkage analyses and association studies have shown that susceptibility to MS is associated with genes in the human histocompatibility leukocyte antigens (HLA) class II region, but the contribution of these genes to MS disease development less compared with their contribution to disorders such as insulin-dependent diabetes mellitus. Due to the strong linkage disequilibrium in the MHC class II region, it has not been possible to determine which gene(s) is responsible for the genetic predisposition. In transgenic mice, we have expressed three human components involved in T-cell recognition of an MS-relevant autoantigen presented by the HLA-DR2 molecule: DRA*0101/DRB1*1501 (HLA-DR2), an MHC class II candidate MS susceptibility genes found in individuals of European descent; a T-cell receptor (TCR) from an MS-patient-derived T-cell clone specific for the HLA-DR2 bound immunodominant myelin basic protein (MBP) 4102 peptide; and the human CD4 coreceptor. The amino acid sequence of the MBP 84-102 peptide is the same in both human and mouse MBP. Following administration of the MBP peptide, together with adjuvant and pertussis toxin, transgenic mice developed focal CNS inflammation and demyelination that led to clinical manifestations and disease courses resembling those seen in MS. Spontaneous disease was observed in 4% of mice. When DR2 and TCR double-transgenic mice were backcrossed twice to Rag2 (for recombination-activating gene 2)-deficient mice, the incidence of spontaneous disease increased, demonstrating that T cells specific for the HLA-DR2 bound MBP peptide are sufficient and necessary for development of disease. Our study provides evidence that HLA-DR2 can mediate both induced and spontaneous disease resembling MS by presenting an MBP self-peptide to T cells. Hide abstract
2002. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat. Immunol., 3 (10), pp. 940-3. Read abstract | Read more
The multiple sclerosis (MS)-associated HLA major histocompatibility complex (MHC) class II alleles DRB1*1501, DRB5*0101 and DQB1*0602 are in strong linkage disequilibrium, making it difficult to determine which is the principal MS risk gene. Here we show that together the DRB1 and DRB5 loci may influence susceptibility to MS. We demonstrate that a T cell receptor (TCR) from an MS patient recognized both a DRB1*1501-restricted myelin basic protein (MBP) and DRB5*0101-restricted Epstein-Barr virus (EBV) peptide. Crystal structure determination of the DRB5*0101-EBV peptide complex revealed a marked degree of structural equivalence to the DRB1*1501-MBP peptide complex at the surface presented for TCR recognition. This provides structural evidence for molecular mimicry involving HLA molecules. The structural details suggest an explanation for the preponderance of MHC class II associations in HLA-associated diseases. Hide abstract
2006. MHC class II proteins and disease: a structural perspective. Nat. Rev. Immunol., 6 (4), pp. 271-82. Read abstract | Read more
MHC class II molecules on the surface of antigen-presenting cells display a range of peptides for recognition by the T-cell receptors of CD4+ T helper cells. Therefore, MHC class II molecules are central to effective adaptive immune responses, but conversely, genetic and epidemiological data have implicated these molecules in the pathogenesis of autoimmune diseases. Indeed, the strength of the associations between particular MHC class II alleles and disease render them the main genetic risk factors for autoimmune disorders such as type 1 diabetes. Here, we discuss the insights that the crystal structures of MHC class II molecules provide into the molecular mechanisms by which sequence polymorphisms might contribute to disease susceptibility. Hide abstract
2005. Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor. Nat. Immunol., 6 (5), pp. 490-6. Read abstract | Read more
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 complementarity-determining 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. Hide abstract