Genetics, Structure, and Function of Histocompatibility Antigens 
RMA-S Mutant Cells 
The RMA-S mutant cell line has been of funda- 
mental importance in understanding peptide an- 
tigen presentation. The cells make MHC class I 
heavy chains and /52-microglobulin, but do not 
display them on their surface. The defect can be 
circumvented by adding synthetic peptides to the 
cells. It is thought to affect either an enzyme that 
cleaves proteins into peptides, or a protein that 
helps transport peptides from the cytoplasm into 
the endoplasmic reticulum, where MHC class I 
molecules fold. 
We have confirmed that these cells are devoid 
of classical MHC class I molecules that can be 
recognized by antibodies or killer T lymphocytes. 
But to our surprise, they still display detectable, 
albeit reduced, amounts of other MHC class I an- 
tigens, such as Mta and Qa- 1 . We infer that either 
these molecules bind their selected peptides 
with much higher affinity than the promiscuous 
classical MHC I molecules, or that these peptides 
are brought to the endoplasmic reticulum by a 
special pathway. 
Most mitochondrial proteins are made in the 
cytoplasm, and much is known about how the 
mitochondria import them, but nothing is known 
about how proteins or peptides escape from the 
mitochondria. The Mta antigen is proof that mito- 
chondrial peptides make it to the cell surface. We 
are now exploring mechanisms that may increase 
the production or release of mitochondrial pro- 
teins and peptides. We use both standard bio- 
chemical assays to test for the release of proteins 
from purified mitochondria and immunological 
assays on intact RMA-S cells to test specifically for 
the NDl peptide. Antibodies against mitochon- 
drial proteins are often present in diseases with 
an autoimmune component, such as primary cir- 
rhosis of the liver. We hope to learn what brings 
about the initial exposure of these mitochondrial 
self-antigens to the immune system. 
Mta in the Rat 
To understand the importance and evolution of 
the Mta system, we look for parallels in other spe- 
cies. We have shown previously that the NDl 
peptide of the rat can be recognized by mouse 
killer T lymphocytes if presented by mouse M3. 
We now know that the rat has its own maternally 
transmitted antigen system, which again involves 
a mitochondrial peptide. It differs in two impor- 
tant respects: the peptide is not from the amino 
terminus of NDl , and it is presented by the classi- 
cal RTIA of the rat, not by a special MHC class I 
molecule. 
The rat, however, does have an expressed MHC 
class I gene like the mouse M3. We have cloned 
and sequenced it. 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 observa- 
tions 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. 
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