Research Topics

Molecular Immunology, Protein Dynamics, Protein Structure, Receptor Biochemistry, Toxins

Disease Research Interests

Cancer, Drug Discovery, Infectious Diseases

B.S. 1975 Illinois State University
Ph.D. 1982 University of Illinois, Urbana-Champaign
Postdoc. 1982-86 Massachusetts Institute of Technology

Structure, Function, and Engineering of T Cell Receptors; Molecular Basis of Immune Recognition by T Cells; Tumor Targeting with T Cells; Engineering Protein Therapeutics

Research in our laboratory is directed toward understanding a fundamental issue in immunology: how mammals can eliminate millions of different antigens that are "foreign" (e.g. viruses, bacteria) without destroying antigens that are "self" (e.g. one's own tissues). The specific focus of the lab is on the antigen-specific receptor expressed by T lymphocytes (T cell receptor, TCR). The TCR is an αβ heterodimer that recognizes foreign peptides that are bound to products of the major histocompatibility complex (MHC). Foreign peptides can be derived from viral or bacterial antigens or in some cases from tumor associated antigens. For example, cytotoxic T cells recognize and kill tumor cells that express on their surface peptides bound to class I products of the MHC. Down regulation of the peptide/class I complex is one mechanism that tumor cells use to escape recognition and destruction. It has also become clear that the aberrant reactivities of some αβ TCRs can have severe autoimmune consequences. Rheumatoid arthritis and multiple sclerosis are two examples of diseases that involve the activity of T cells. Studies of the molecular processes involved in the expression of the αβ TCR and the biochemical interactions between the TCR and its ligands are essential to understanding and eventually controlling such detrimental responses.

A complete understanding of T cell recognition will require knowledge about the binding properties of T cell receptors. Unfortunately, the major limitation to such biochemical analyses has been the lack of pure receptor
protein. Our lab has engineered a "single-chain receptor" gene (scTCR) that contains the  Vα and Vβ genes from a T cell clone linked by a gene that encodes a flexible peptide. The scTCR has been overexpressed in E. coli and a product of the appropriate molecular weight (~27 kD) has been identified. Our goals are to use these recombinant proteins to: 1) evaluate the binding affinities and specificities of the TCR, 2) use site-directed mutagenesis to map the binding site of the TCR, and 3) correlate the energy of TCR-peptide/MHC interactions with biological function. In another project, the TCR has been displayed on the surface of yeast cells. The yeast display system has been used to evolve more stable forms of the soluble TCR and to evolve TCR with higher affinities for their ligands. These high affinity TCRs have been used 1) to study the relationship between T cell function and TCR:ligand binding kinetics, 2) as probes for the presence of peptide-MHC complexes on tumor cells, 3) to inhibit undesirable T cell activity, and 4) to elucidate the structural contributions of different interactions to binding affinity.

Finally, our lab is interested in engineering other proteins of immunological
interest. These include the class I and class II MHC proteins, NK receptors, and antibodies against various T cell surface molecules. Proteins engineered for greater stability and higher affinity will be used to examine various structural and biochemical properties of the proteins, in addition to develop possible novel therapeutic agents.

Department of Biochemistry
600 S Mathews Ave
Urbana, IL 61801