Present Position and Address

Department of Microbiology & Immunology
Scientist, Sealy Center for Molecular Science
The University of Texas Medical Branch
Galveston, TX 77555-1070
Phone: (409) 772-6612, 747-0395
FAX: (409) 747-6869
E-mail: rokonig@utmb.edu

1980 University of Bern, Switzerland Master of Science Biology
1984 University of Bern, Switzerland Ph.D. Biology

RESEARCH INTERESTS:

Molecular and cellular analysis of T lymphocyte activation, differentiation and apoptosis.

Structure-function analysis of T cell coreceptors (CD4, CD5) and their ligands.

Immunomodulation in vivo and in vitro.

Research activities in this laboratory concentrate on elucidating the molecular events that regulate T lymphocyte activation and tolerance, and the differentiation of T lymphocytes into functional subsets. T lymphocytes initiate immune responses after interaction of the antigen-specific T cell receptor (TCR) with antigenic peptide presented by molecules of the major histocompatibility complex (MHC). Whether the resulting cellular response leads to proliferation of T lymphocytes and production of cytokines, or to T cell tolerance depends on coreceptor and costimulatory molecules that must interact with their respective ligands to enhance and modify TCR-mediated signals.

Current projects focus on defining the molecular basis for the interaction between two coreceptor-ligand pairs; one between the T cell coreceptor CD4 and MHC class II molecules on antigen-presenting cells, the other between the T cell coreceptor CD5 and CD72. CD4 is a membrane glycoprotein on T lymphocytes that respond to peptide antigens associated with MHC class II molecules. CD4 binds to the same MHC class II molecule recognized by the TCR, thereby stabilizing interactions between the TCR and peptide:MHC class II complexes and promoting the localization of the src family tyrosine kinase p56lck into the receptor complex. Using site-directed mutational analysis and T cell functional assays, we have defined two regions on MHC class II molecules that regulate the interaction with CD4. To define the precise orientation of CD4-MHC class II interfaces during binding, we have generated protein domains of CD4 and MHC class II. These genetically engineered proteins are overexpressed in bacteria in order to ultimately determine the exact structural requirements for their interaction by nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography.

Intracellular signalling events in T cells are initiated by interactions of cell surface receptors with their ligands. Interactions between CD4 and MHC class II molecules, and between CD5 and CD72 during antigen-induced T cell activation modulate signal transduction via the TCR. We determine the molecular events following antigenic stimulation in the presence or absence of coreceptor function using immunoprecipitation and protein phosphorylation assays, by measuring intracellular calcium concentrations, and by analyzing the induction of nuclear DNA-binding proteins. Knowledge of the structural basis for the interaction between CD4 and MHC class II molecules can help in designing immunomodulating agents. Such agents may be useful in preventing or reversing autoimmune reactions that are mediated by CD4+ T cells (e.g., insulin-dependent diabetes mellitus, rheumatoid arthritis, myasthenia gravis, multiple sclerosis, and systemic lupus erythematosus). For example, peptides corresponding to the CD4-interacting regions of MHC class II molecules can block primary T cell responses in vitro. The same peptides can prevent antigen-induced T cell tolerance in vivo. Therefore, we are testing their potential to augment immune responses directed against pathogenic organisms and malignant cells.

Techniques regularly used in this laboratory include recombinant DNA technology, gene transfer, protein biochemistry, and cellular immunology in vitro and in vivo.

1. D. P. Metz, D. L. Farber, R. König, and K. Bottomly (1997) Regulation of memory CD4 T cell adhesion by CD4-MHC class II interaction. J. Immunol. 159: 2567-2573.
2. X. Shen and R. König (1998) Regulation of T cell immunity and tolerance in vivo by CD4. Int. Immunol. 10: 247-257.
3. S. Gilfillan, X. Shen, and R. König (1998) Selection and function of CD4+ T lymphocytes in transgenic mice expressing mutant MHC class II molecules deficient in their interaction with CD4. J. Immunol. 161: 6629-6637.
4. L. Wang, J. J. Y. Chen, B. B. Gelman, R. König, and M. W. Cloyd (1999) A novel mechanism of CD4 lymphocyte depletion involves HIV’s effects on resting lymphocytes: induction of lymph node homing and apoptosis upon secondary signaling through homing receptors. J. Immunol. 162: 268-276.
5. R. Maroto, X. Shen, and R. König (1999) Requirement for efficient interactions between CD4 and MHC class II molecules for survival of resting CD4+ T lymphocytes in vivo and for activation-induced cell death. J. Immunol. 162: 5973-5980.
6. X. Shen and R. König (2001) Post-thymic selection of peripheral CD4+ T lymphocytes on class II major histocompatibility antigen-bearing cells. Cell. Mol. Biol. 47: 87-96.
7. X. Shen, K. Lee, and R. König (2001) Effects of heavy metal ions on resting and antigen-activated CD4+ T cells. Toxicology 169: 67-80.
8. K. Lee, X. Shen, and R. König (2001) Effects of cadmium and vanadium ions on antigen-induced signaling in CD4+ T cells. Toxicology 169: 53-65.
9. R. König, X. Shen, R. Maroto, and T. L. Denning (2002) The role of CD4 in regulating homeostasis of T helper cells. Immunol. Res. 25:115-130.
10. R. König (2002) Interactions between MHC molecules and co-receptors of the TCR. Curr. Opin. Immunol. 14: 75-83.