Areas of Interest
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.
Publications
Selected Publications
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.
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