Mechanisms of Antigen Presentation 
C. Geoffrey Davis, Ph.D. — Assistant Investigator 
Dr. Davis is also Assistant Professor of Medicine and of Microbiology and Immunology at the University of 
California, San Francisco. He received his B.A. degree in biology from Swarthmore College and his Ph.D. 
degree in immunology from UCSF. He did his postdoctoral research in the laboratory of Joseph Goldstein 
and Michael Brown at the University of Texas Health Science Center at Dallas. 
THE two key features of the immune system 
are diversity and specificity. While it must be 
capable of recognizing a large array of pathogens, 
it must subsequently mount a specific and appro- 
priate response to each. Diversity is accom- 
plished at the level of the cell surface receptors 
on T and B lymphocytes. Specificity is accom- 
plished at several levels, the first of which is in 
the intracellular proteolytic processing of the 
pathogen. This processing results in the genera- 
tion of peptide fragments, which then bind to ei- 
ther class I or class II products of the major histo- 
compatibility complex (MHC). 
The choice of class I or class II MHC molecule 
is determined by the nature of the pathogen. In 
general, peptide fragments derived from patho- 
gens that have entered the cell from outside, like 
most bacteria, bind to class II molecules, while 
fragments derived from pathogens that use the 
cell's replicative machinery to proliferate, like 
viruses, bind to class I molecules. Once bound, 
the fragment is transported to the cell surface, 
where it can be recognized by an effector T 
lymphocyte. 
The type of T lymphocyte responding is closely 
linked to the type of MHC molecule presenting 
the peptide. Thus a peptide bound to a class II 
molecule will stimulate a helper T cell, which in 
turn will trigger the production of antibodies. In 
contrast, a peptide bound to a class I molecule 
targets the presenting cell for destruction by stim- 
ulating a cytotoxic T lymphocyte. Our research 
focuses on various aspects of the intracellular 
processes that allow class I MHC molecules to 
distinguish endogenously synthesized pathogens 
from those that have been taken up from outside. 
The mature class I molecule is a heterodimer 
consisting of a transmembrane heavy chain non- 
covalently associated with a soluble light chain. 
Studies with mutant cell lines have revealed that 
the assembly of class I heterodimers takes place 
in the endoplasmic reticulum and is tightly regu- 
lated. These studies have shown that the peptide 
itself plays a role in determining the fate of the 
complex. Thus class I molecules that have suc- 
cessfully bound a peptide are transported to the 
cell surface, while those that have failed to bind a 
peptide dissociate and are degraded within the 
cell. This implies that there is an intracellular 
"gate" that distinguishes heterodimers that have 
bound peptide — and are therefore functional — 
from those that have not. To gain insight into the 
mechanism behind this gate, Rebecca Elstrom has 
studied the assembly process in an in vitro sys- 
tem. She has succeeded in inducing class I heavy 
and light chains, which have been synthesized in 
vitro, to assemble within membrane vesicles de- 
rived from the endoplasmic reticulum. The re- 
sults of her studies indicate that in an oxidizing 
environment, which is the physiological state of 
the endoplasmic reticulum, stable heterodimers 
are formed even in the absence of peptide. In 
contrast, in a reducing environment, stable het- 
erodimers are formed only when peptide is 
added. These findings suggest that class I hetero- 
dimers form in the endoplasmic reticulum inde- 
pendent of peptide. Subsequently, while en 
route to the surface, they may encounter an intra- 
cellular compartment with a reducing environ- 
ment. In this compartment, only heterodimers 
that have bound peptide remain intact and are 
allowed to proceed to the cell surface, while 
those that have not bound peptide dissociate. 
This in vitro system holds great promise for pro- 
ducing further insights into assembly of class I 
complexes. 
Studies initiated by Michael Zegans, a Howard 
Hughes Medical Scholar, and being pursued by 
Rabin Chakrabarti, a Howard Hughes Associate, 
focus on a special problem in antigen presenta- 
tion, that of intracellular parasites. Such parasites 
replicate within the host cell but use their own 
machinery to do so. Although they might be ex- 
pected to shed proteins into the cytoplasm where 
they would be exposed to proteolysis and thus to 
presentation by class I molecules, the occurrence 
of class I-restricted immune responses has, for 
many parasites, been difficult to demonstrate. 
Chlamydia trachomatis, a leading cause of 
blindness in the world, is an organism particu- 
larly suitable for such studies, since more than 
half of its entire mass is contributed by a single 
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