Cytotoxic T Lymphocyte Recognition 
Michael J. Sevan, Ph.D. — Investigator 
Dr. Bevan is also Professor of Immunology at the University of Washington, Seattle. He received his Ph.D. 
degree for work performed at the National Institute for Medical Research, Mill Hill, london. He did his 
postdoctoral work at the Salk Institute in the laboratory of Melvin Cohn, after which he was a faculty 
member in the Center for Cancer Research and the Department of Biology at the Massachusetts Institute 
of Technology. He later conducted research in immunology at the Scripps Research Institute before moving 
to the University of Washington. Dr. Bevan was elected Fellow of the Royal Society of london. 
TWO functionally different types of T lympho- 
cytes mature in the thymus and populate the 
peripheral lymphoid organs. Helper T lympho- 
cytes, the first type, respond to antigen by releas- 
ing lymphokines, which activate macrophages or 
augment the response of antibody-producing B 
cells. Cytotoxic T lymphocytes, on the other 
hand, when induced with antigen, specifically 
lyse target cells expressing the antigen and re- 
lease interferon-7. Their function is thought to be 
crucial in the response to intracellular patho- 
gens, such as viruses and bacteria, and they may 
eliminate some tumor cells. 
T lymphocytes can only recognize antigen pre- 
sented in association with cell surface glycopro- 
teins encoded by the major histocompatibility 
complex (MHC) . Recent work has shown that cy- 
totoxic T cells recognize short (usually nona- 
meric) antigenic peptides presented in the 
groove of class I MHC molecules. 
Since class I molecules are expressed on vir- 
tually all tissues, any cell type can be a target for 
cytotoxic cells. The peptides presented by these 
MHC molecules derive from degraded intracellu- 
lar proteins, so all, or most, of a cell's normal 
components can provide class I-binding pep- 
tides. Normally, however, the T cells tolerate 
these self-peptide/self-MHC complexes. Viral in- 
fection, on the other hand, leads to the produc- 
tion of new proteins in the cell. These may pro- 
vide nonamer peptides that can combine with 
class I and be presented on the surface. If cyto- 
toxic T lymphocyte surveillance works well, 
these foreign-peptide/self-MHC complexes will 
be recognized and the virus-infected cell 
destroyed. 
The class I MHC proteins expressed on the cell 
surface have three components: class I heavy 
chain, (82microglobulin, and a tightly bound 
peptide. This trimolecular complex is assembled 
shortly after synthesis of the heavy and light 
chains in a pre-Golgi compartment. 
Many of the peptides that are bound to class I 
actually derive from cytosolic and nuclear pro- 
teins. It seems likely that cytosolic proteins are 
degraded in the cytosol by complex structures 
called proteosomes and that the peptide degrada- 
tion products pass into the endoplasmic reticu- 
lum (ER). Some of the components of proteo- 
somes are encoded within the MHC in close 
proximity to a pair of genes that belong in the 
superfamily of ATP-dependent transport pro- 
teins. These gene products may mediate the 
translocation of peptide antigen from the cyto- 
plasm into the ER lumen. 
Antigen Presentation-Defective Variants 
A number of mouse and human cell lines have 
been described that synthesize normal class I 
heavy and /32-microglobulin chains but neither as- 
semble these chains for surface expression nor 
present endogenous antigens to cytotoxic T cells. 
We provided evidence that the defect in the 
mouse cell line RMA-S maps to chromosome 17, 
the chromosome encoding the MHC. When this 
cell line was fused with a wild-type partner, ex- 
pression of MHC antigens was restored. When the 
wild-type chromosome 17 was selected against, 
expression of the MHC antigens was lost. John 
Monaco (Virginia Commonwealth University, 
Richmond) had previously identified and cloned 
Ham l and Ham-2, two ABC transporter genes 
from the mouse MHC. In collaboration with his 
group and with James Forman and Kirsten Fischer 
Lindahl (HHMI, University of Texas Southwest- 
ern Medical Center at Dallas), we were able to 
show that transfection of the Ham-2 gene into 
RMA-S restored surface expression of class I MHC 
antigens, as well as the ability to present five en- 
dogenous antigens on the surface for recognition 
by cytotoxic T lymphocytes. Thus a defect in the 
Ham-2 gene leads to loss of surface class I ex- 
pression. In conjunction with previous experi- 
ments with the human defective cell lines, this 
suggests that both Ham- 1 and Ham-2 may be es- 
sential for class 1 surface expression, and in fact 
they may operate as heterodimers. 
In other experiments we have shown that the 
RMA-S cell line expresses a subset of endogenous 
peptides on the surface with class 1. For example, 
the octameric peptide derived from the vesicular 
stomatitis virus nucleoprotein is presented to cy- 
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