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Genetics, Structure, and Function 
of Histocompatibility Antigens 
Kirsten Fischer Lindahl, Ph.D. — Investigator 
Dr. Fischer Lindahl is also Professor of Microbiology and Biochemistry at the University of Texas 
Southwestern Medical Center at Dallas. She began the study of histocompatibility with Morten Simonsen 
in Copenhagen, Denmark, and received her Ph.D. degree in immunobiology from the University of 
Wisconsin-Madison. She was a postdoctoral fellow with Darcy Wilson at the University of Pennsylvania, 
Philadelphia, and with Klaus Rajewsky at the Institute for Genetics in Cologne, West Germany. Before 
accepting her current position, she was a member of the Basel Institute of Immunology in Switzerland. 
HISTOCOMPATIBILITY (H) antigens are cell 
surface molecules that, when foreign, lead 
to the rejection of grafted tissues and organs by 
the vertebrate immune system. Because they form 
a major obstacle to clinical transplantation, H an- 
tigens have been studied for over 50 years. They 
are complexes of a small peptide ligand and an 
MHC molecule (encoded by genes of the major 
histocompatibility complex). A given individual 
has MHC molecules of a few different kinds, each 
of which can present to the immune system a 
large variety of peptides on the surface of cells. 
These peptides might be derived from proteins 
produced by intracellular parasites, bacteria, or 
viruses or by the body's own cells, such as tumor- 
specific antigens or minor H antigens. The amino 
acid side chains that line the peptide-binding 
groove of an MHC molecule determine which 
peptides that molecule can bind and therefore 
what antigens can be presented to induce an im- 
mune response in the individual with this MHC. 
The immune system is capable of recognizing a 
difference in either of the H antigens' two parts. A 
difference in the MHC molecule itself will alter 
many complexes and induce a strong immune re- 
sponse, hence the term "major" H antigen. By 
contrast, a difference in a peptide alters only one 
of many kinds of complexes and induces a weaker 
response, hence the term "minor" H antigen. Un- 
like the major H antigens, human minor H anti- 
gens remain ill defined. In the mouse, however, 
more than 50 genes that encode minor H antigens 
have been mapped. Almost every chromosome, 
including the mitochondrial genome, carries at 
least one. 
The Maternally Transmitted Antigen 
In the mouse mitochondrial protein NDl, the 
sixth amino acid is polymorphic. When cells with 
one form are transplanted to a mouse with an- 
other form, the amino-terminal peptide of NDl 
will act as a transplantation antigen, called Mta. 
This peptide is presented on the cell surface by 
an MHC class I molecule called M3. M3 binds the 
NDl peptide only when the methionine at the 
end carries a formyl group, and M3 can also bind 
other peptides with a formyl-methionine. This 
characteristic of the amino terminus of mito- 
chondrial and bacterial proteins distinguishes 
them from proteins made in the cytoplasm of 
mammalian cells. We are collaborating with 
Michael Bevan (HHMI, University of Washington, 
Seattle) , who is studying the immune response of 
mice to the bacterium Listeria. His group reports 
that the M3 molecules present a Listeria antigen 
on the cell surface to cytotoxic T cells, which kill 
the infected cells. 
It is of great interest to understand how the 
formyl-methionine peptides are bound by M3 and 
which amino acids in M3 are important for this 
specificity. We cloned the gene for M3 from mice 
and rats. The rat and mouse M3 genes are more 
similar to each other than they are to the other 
MHC class I genes of their own species. This is 
particularly striking in the rat, where the class I 
genes are otherwise very similar. These results 
suggest that the specialized function of M3 
evolved long ago in a species from which both 
rats and mice are descended, and that it has been 
conserved in both species during their separate 
evolution, presumably because it is useful in the 
immune response against bacterial peptides. 
We can express M3 in mouse fibroblasts, where 
Mta can be detected by killer T lymphocytes. This 
system allows us to change single amino acids in 
the protein by introducing mutations at specific 
sites in the gene. We are currently looking at 
amino acids 34 and 171, which differ in M3 from 
the consensus of MHC class 1 molecules and are 
near the site where the formyl-methionine of the 
peptide is expected to lodge. In sequencing natu- 
rally occurring variants of the M3 gene from wild 
mice, we are learning more about which amino 
acids are essential for the ability to present the 
NDl peptide. Amino acid 95 points straight up in 
the peptide-binding site, probably right under 
the variable sixth residue of the peptide. The sin- 
gle change of 95 from leucine to glutamine com- 
pletely abolishes T cell recognition of Mta. We 
are collaborating with the laboratory of Johann 
Deisenhofer (HHMI, University of Texas South- 
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