Most cells of the body express class I major histocompatibility complex molecules, or MHC molecules. As shown in the figure below, class I MHC molecules bind and "present" on the cell surface small peptides derived from proteins produced within the cell as a way to show on the oustide what kind of proteins are being made on the inside.

The complex between peptides and class I MHC molecules are recognized by T cell receptors (TCRs) expressed on the surface of cytotoxic T lymphocytes. Given the proper conditions and other necessary molecular interactions, provided the interaction between a TCR and peptide/MHC is of sufficient strength, recognition of a peptide/MHC by a TCR results in the destruction of the antigen presenting cell.

As diagrammed below, one role of this arm of the immune system is to destroy virally infected cells actively making viral proteins. Another role is to recognize and destroy pre-malignant cells in a process termed cancer immunosurveillance. Recognition of an antigen presented by a class I MHC molecule does not always result in cell killing; T cell recognition of peptide/MHC is also crucial in T cell development, as well as the survival or "maintenance" of the immune system. T cell recognition of antigens presented by class I MHC molecules is also important in autoimmunity and transplant rejection.

gnition of peptide/MHC. One involves elucidating the physical principles behind T cell receptor recognition and specificity. In the simple diagram above, a TCR is shown recognizing a viral peptide. Yet T cell receptors are "cross-reactive" - capable of recognizing a variety of peptides with a range of affinities and kinetics. This has significant consequences for the development of the immune system, the immune responses to pathogens and cancer, as well as autoimmunity. Understanding the physical determinants behind TCR specificity and cross-reactivity is a major focus of our work. We are using a variety of biophysical approaches, aiming to understand the distribution of binding energies in these interfaces as well as the role of protein and peptide dynamics in influencing cross-reactivity and specificity.

In another project, we are studying ways to improve immunologically-based cancer therapeutics. Although cancer immunosurveillance is an important function of the immune system, the "tumor associated antigens" against which the immune system can react are often poorly presented by class I MHC molecules, resulting in a poor or non-existent immune response. However, if tumor-reactive T cells can be "primed" an immune response can be initiated. We are investigating ways in which tumor associated antigens can be modified to improve their affinity to class I MHC molecules, enhancing their immunogenicity. We are also investigating the properties of T cell receptors that have shown to be highly tumor reactive in clinical studies, aiming to understand what TCR properties distinguish a strongly tumor reactive T cell from a poorly tumor reactive T cell and how to improve the strategy of creating genetically engineered immune systems for cancer patiens (the Cancer Research Institute has a put together an excellent primer that describes the various aspects of cancer immunology we are interested in, and Time magazine recently ran a story describing the work of some of our collaborators and the promise of cancer immunology).

Techniques used in the lab include structural biology, both protein crystallography and high field NMR, as well as physical measurements of binding thermodynamics and kinetics. We use a variety of methods and analytical approaches, including surface plasmon resonance, calorimetry, steady state and time resolved fluorescence anisotropy, circular dichroism spectroscopy, and analytical ultracentrifugation. Structural biology experiments are usually performed at the Advanced Photon Source at nearby Argonne National Laboratory, or locally using NMR resources within the Lizzadro Magnetic Resonance Research Center. We also make use of computational biochemistry, including molecular dynamics simulations and continuum electrostatic calculations, and perform cell culture-based immunological assays. Behind all of the work is a considerable amount of molecular biology, recombinant protein expression, and various types of protein chemistry.