Research Description

Overall Philosophy of the Teyton Laboratory

The Teyton laboratory is not focused on a particular technique or approach. To the contrary, the work is focused on obvious, important biological questions that are relevant to physiology and pathology. Any technical mean needed will be applied to answer the question. Many of the techniques have been developed in the laboratory but collaboration with experts in various fields remains the modus operandi and the key to success. With this in mind, any member of the group will be exposed to biochemistry, structural biology, biophysics, gene knockout, transgenesis, cell biology, chemistry, or any other aspect of science that may be needed to succeed in her or his project. The same approach applies within the laboratory where collaboration and sharing of techniques and reagents are highly encouraged. Writing and presentation skills are practiced and reviewed for all members of the laboratory. All projects are related to a disease area and have a pre-clinical component to them.

Tea is every day at 5:00. Running and/or biking are not expected but encouraged.

1)  T Cell Receptor Activation

The expression of a recombinant T cell receptor (TCR) and the determination of its structure were carried out in our laboratory between 1994 and 1996 (collaboration with Ian Wilson). The original goal of the work was to understand the molecular mechanism of TCR activation. The structures of the TCR by itself and in complex with pMHC did not reveal any major structural rearrangement or conformational change that could support signal transduction. We reasoned that the organization of the higher order TCR complex that includes TCR as well as CD3δε and γε dimers, was probably needed to decipher the molecular basis of activation. For the past 15 years we have used protein engineering to try to express a soluble and secreted form of TCR-CD3 that would be amenable to structural studies. Recent successes in this direction have allowed us to initiate electron microscopy as well as crystallographic studies of the TCR complex alone and in complex with pMHC and co-receptors. Small chemical compounds capable of binding TCR and CD3 have also been isolated from large chemical libraries to help with this structural effort and to try to design new immunosuppressive drugs.

2)  Major Histocompatibility Molecules and Autoimmunity

The link between HLA genes and autoimmunity was uncovered 30 years ago. No mechanistic explanation has been provided for this association, yet. In the context of type 1 diabetes, the association between disease and HLA is limited to a single polymorphism at position 57 of the β chain where a normal aspartic acid is replaced by a serine or an alanine, creating a positively charged exposed surface patch. We have determined that this alteration of the MHC molecule was leading the selection of T cell receptors capable of recognizing this part of the MHC. As a consequence, the affinity of these particular TCRs is increased. We have now, using a combination of transgenic and knockout animals, demonstrated that this unique mode of MHC recognition by TCR was relevant in vivo for the development of disease. This discovery allows the rational design of anti-HLA-DQ8 antibodies and small molecules as a therapeutic approach for the prevention of autoimmunity in type 1 diabetes.

3)  CD1 Molecules and Lipid Presentation

Lipids and glycolipids are recognized by T cells when presented by MHC-like molecules called CD1. We have studied presentation and recognition of lipid antigens for two decades, focusing our interests on a small population of regulatory T cells called NKT cells. These cells are of particular interest in immunology and therapeutics because they regulate the initial phase of all immune responses by controlling the differentiation of dendritic cells, the recruitment of NK cells, CD4 and CD8 T cells, and helping directly B cells in their maturation. These studies have led to a large body of work that examined the thymic selection of NKT cells, their peripheral mode of activation, the loading of glycolipids onto CD1, and finally the identification of the natural endogenous ligands that allow selection and activation of these cells. We have experimented the activation of NKT cells in human as an adjuvant of immunity. Whilst, the effect was remarkable on the breadth and amplitude of the immune response, transport to the liver of the activating glycolipids led to side effects. We are currently exploring new delivery modes to limit transport to the liver, or, as an alternative approach, the in vivo modulation of endogenous ligands by inhibition of their catabolic enzymes.

4)  Vaccination

The efforts of developing vaccines against microbes that spontaneously do not lead to protective immunity have been disappointing. The limitations of the empirical way of developing vaccines will only be overcome if we translate our understanding of antigen presentation, coordination of CD4, CD8 and B cell responses, and elicitation of T and B cell memory to the design of the components that are mixed together to produce synthetic vaccines. We have examined these challenges in the most difficult context of trying to produce anti-glycan-based vaccines. Glycan are the prototypic T cell-independent antigens. We have decided to render them (the glycans), T cell-dependent by allowing their direct presentation to T cells. We have succeeded in this approach for two prototypic microbial sugars and elicited high affinity, protective and long-lasting immune responses specific of each microbe. The same approach is now used to develop potential vaccines against a host of emerging pathogens. The basic immunological principles that support this approach are studied at the structural level.