The general goals of the laboratory have been to understand the regulation of Major Histocompatibility Complex (MHC) class I gene expression in neoplastic and virally-infected cells. Within the broad context of this interest, the objective has been to determine the structural basis by which b2microglobulin (b2m), a small molecular weight subunit of the MHC class I complex, regulates antigen presentation. What is the significance of this area of study? To answer this question it is important to understand the role of MHC class I molecules in the immunobiology of T cell function. The ability of cytotoxic T cells to recognize and react against foreign antigen-bearing cells is based on the extent to which MHC class I molecules are expressed on the membrane surface of the target cell population. b2m serves a central role in MHC class I biogenesis since its expression is required for the folding of the class I heavy chain as a necessary step in the exocytosis of the MHC class I ternary complex. Understanding the molecular basis by which b2m modulates the expression of MHC class I molecules is likely to provide insight into the modulation of CTL-mediated effector responses. The general approach of these studies has been to produce structural variants of human b2m in a tissue culture-adapted b2m-null human tumor cell line for analysis of the assembly and stability of MHC class I complexes. As a by-product of many of these investigations, considerable insight has been gained on the structural basis of antigenic expression by the MHC class I molecular complex, information with potential impact on modulation of transplantation.

While a basic understanding of MHC class I regulation serves as the underpinning of this research program, more recent interests are directed at an applied molecular appreciation of altered MHC class I in viral infection. The molecular mechanisms by which the herpes viruses escape immune detection remains an area of considerable importance, especially for those member viruses which are known to be the cause of life threatening diseases. In this context, understanding the cellular basis by which the immune system recognizes and reacts against HCMV-infected cells is fundamental to developing an effective strategy of viral regulation and elimination. With these goals in mine, we are presently designing strategies to examine alterations that may occur in the immunological properties of HCMV-infected cells of the central nervous system.

Finally, based upon the evolving role for medical and graduate school instruction in immunology, another area of interest is the development of new approaches to graduate education in the biology and pathophysiology of host defense reactions and immunologic disease. The strategy of problem-based learning in conjunction with the genesis of interdisciplinary elective programs continues to be explored for the development of high quality learning modalities in basic and medical immunobiology.

Tatake, R., Trymbulak, W.P., Jr. and Zeff, R.A. MHC class I heavy chain-dependent expression of discontinuous epitopes on b2microglobulinb is inducible with peptide ligand. Transplantation 59:124-130, 1995.

Tatake, R. and Zeff, R.A. Failure in expression of structurally altered (Cys164®Tyr) H-2Kb molecules is mitigated with high affinity peptide-ligand. Transplantation 59: 1343-1349, 1995.

Zeff, R.A. b2microglobulin in transplantation. Transplantation 60:215-220, 1995.

Trymbulak, W.P., Jr. and Zeff, R.A. Mutants of human b2-microglobulin map an immunodominant epitope within the three-stranded beta-pleated sheet. Transplantation 64:640-645, 1997.

Trymbulak, W.P., Jr. and Zeff, R.A. Expression of HLA class I molecules assembled with structural variants of human b2-microglobulin. Immunogenetics 46:418-426, 1997.

Wei, C., Zeff, R.A. and Goldschneider, I. Murine pro-B cells require IL-7 and its receptor complex to up-regulate IL-7R alpha, terminal deoxynucleotidyl transferase, and c mu expression. Journal of Immunology 164:1961-1970, 2000