David M Kranz

d-kranz@illinois.edu

352C Burrill Hall
Office: (217) 244-2821
Lab: (217) 244-2823
Fax: (217) 244-5858

Mail to: Department of Biochemistry
600 S Mathews Ave
Urbana, IL 61801
Video Interview

David M Kranz

Professor of Biochemistry
Phillip A. Sharp Professor

Research Topics

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

Education

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

Teaching Interests

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 α&beta 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.

Representative Publications

Stone JD, Chervin AS, Aggen DH, Kranz DM. T cell receptor engineering. Methods Enzymol. 2012;503:189-222.

Engels, B., A. S. Chervin, A. J. Sant, D. M. Kranz, and H. Schreiber (2012) Long-term Persistence of CD4(+) but Rapid Disappearance of CD8(+) T Cells Expressing an MHC Class I-restricted TCR of Nanomolar Affinity. Molecular Therapy. 20(3):652-60.

Aggen, D. H., A. S. Chervin, T. M. Schmitt, B. Engels, J. D. Stone, S. A. Richman, K. H. Piepenbrink, B. M. Baker, P. D. Greenberg, H. Schreiber, and D. M. Kranz (2012) Single-chain ValphaVbeta T-cell receptors function without mispairing with endogenous TCR chains. Gene Therapy, 19(4):365-74.

Stone, J. D., D. H. Aggen, A. S. Chervin, S. Narayanan, T. M. Schmitt, P. D. Greenberg, D. M. Kranz (2011) Opposite effects of endogenous peptide-MHC class I on T cell activity in the presence and absence of CD8. J Immunol. 186(9):5193-200.

Aggen, D. H., A. S. Chervin, F. K. Insaidoo, K. H. Piepenbrink, B. M. Baker, and D. M. Kranz (2011) Identification and engineering of human variable regions that allow expression of stable single-chain T cell receptors. Protein Eng Des Sel. 24(4):361-72.

Thomas, D. L., R. Doty, V. Tosic, J. Liu, D. M. Kranz, G. McFadden, A. L. Macneill, and E. J. Roy (2011) Myxoma virus combined with rapamycin treatment enhances adoptive T cell therapy for murine melanoma brain tumors. Cancer Immunol Immunother. 60(10):1461-72.

Bonsor, D. A., S. Postel, B. G. Pierce, N. Wang, P. Zhu, R. A. Buonpane, Z. Weng, D. M. Kranz, E. J. Sundberg (2011) Molecular basis of a million-fold affinity maturation process in a protein-protein interaction. J Mol Biol. 411(2):321-8.

Fuertes, M. B., A. K. Kacha, J. Kline, S. R. Woo, D. M. Kranz, K. M. Murphy, and T. F. Gajewski (2011) Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J Exp Med. 208(10):2005-16.

Stone, J. D., M. N. Artyomov, A. S. Chervin, A. K. Chakraborty, H. N. Eisen, and D. M. Kranz (2011) Interactions of streptavidin-based peptide-MHC oligomers (tetramers) with cell-surface T cell receptors. J Immunol. 187(12):6281-90.

Adams, J. J., S. Narayanan, B. Liu, M. E. Birnbaum, A. Kruse, N. A. Bowerman, W. Chen, A. M. Levin, J. M. Connolly, C. Zhu, D. M. Kranz, and K. C. Garcia (2011) T cell receptor signaling is limited by docking geometry to peptide-Major Histocompatibility Complex. Immunity. 35(5):681-93.

Persaud, S. P., D. L. Donermeyer, K. S. Weber, D. M. Kranz, and P. M. Allen (2010) High-affinity T cell receptor differentiates cognate pepMHC and altered peptide ligands with distinct kinetics and thermodynamics. Mol Immunol. 47(9):1793-801.

Wang, N, D. M. Mattis, E. J. Sundberg, P. M. Schlievert, and D. M. Kranz (2010) A single, engineered protein therapeutic neutralizes exotoxins from both Staphylococcus and Streptococcus. Clin Vaccine Immunol. 17(11):1781-9.

Cho, S, C. P. Swaminathan, D. A. Bonsor, M. C. Kerzic, R. Guan, J. Yang, M. C. Kieke, P. S. Andersen, D. M. Kranz, R. A. Mariuzza, and E. J. Sundberg (2010) Assessing energetic contributions to binding from a disordered region in a protein-protein interaction. Biochemistry. 49(43):9256-68.

Strandberg, K. L., J. H. Rotschafer, S. M. Vetter, R. A. Buonpane, D. M. Kranz, P. M. Schlievert (2010) Staphylococcal superantigens cause lethal pulmonary disease in rabbits. J Infect Dis. 202(11):1690-7.

Chervin, A. S., J. D. Stone, N. A. Bowerman, and D. M. Kranz (2009) Cutting edge: Inhibitory effects of CD4 and CD8 on T cell activation induced by high-affinity noncognate ligands. J Immunol. 183(12):7639-43.

John, C. C., M. Niermann, B. Sharon, M. L. Peterson, D. M. Kranz, and P. M. Schlievert (2009) Staphylococcal toxic shock syndrome erythroderma is associated with superantigenicity and hypersensitivity. Clin Infect Dis. 49(12):1893-6.

Complete Publications List