Mechanisms of Antigen Processing 
cover additional details of the mechanisms in- 
volved in the in vivo generation of class I MHC- 
peptide complexes. 
Class II MHC-Peptide Association 
Class II MHC molecules associate late in trans- 
port with peptides derived from internalized pro- 
tein antigens. It is believed that in the early stages 
of transport, they follow the same pathway as 
class I molecules, namely from the ER through 
the Golgi complex. This leads to the question. 
Why do class II molecules nothind peptides from 
the same set of cytosolically derived peptides that 
associate with class I MHC molecules? 
At least a partial answer lies in the association 
of class II molecules with an additional glycopro- 
tein, the invariant chain. This molecule is not a 
product of the MHC and is not structurally related 
to class I or class II glycoproteins. It associates 
with class II molecules immediately upon synthe- 
sis in the ER, forming a large nine-chain structure 
that we have found to consist of a core trimer of 
invariant chains associated with three class II mol- 
ecules, each of which is a two-subunit hetero- 
dimer. Class II molecules in this structure cannot 
bind antigenic peptides, though they acquire the 
capacity to do so if released by mild denaturation 
or partial proteolysis of the invariant chain. Pre- 
sumably their association with the invariant chain 
in vivo prevents class II MHC molecules 
from binding inappropriate peptides early in 
transport. 
After assembly, the nine-chain class II MHC- 
invariant chain complex is transported from the 
ER and through the Golgi apparatus. We have 
found that the invariant chain then targets the 
complex to endosomal structures, where it en- 
counters internalized foreign antigens, shown 
strikingly when influenza virus is used as a test 
antigen . Evidence obtained with proteinase inhib- 
itors, such as leupeptin, suggests that the invari- 
ant chain is proteolytically degraded in the endo- 
some, releasing class II molecules capable of 
binding peptides. 
The simplest model for the generation of class 
II MHC-peptide complexes suggests that internal- 
ized proteins are endosomally degraded into pep- 
tides that bind to the newly released class II 
molecules. Recent evidence, however, suggests 
that this model is too simple. We have found 
that the T2 cell line, referred to above as a class I 
MHC antigen-processing mutant, is also a class 
II MHC antigen-processing mutant. T2 itself lacks 
class II molecules as a result of the homozygous 
deletion of the MHC region encoding class II mol- 
ecules. However, if mouse class II molecules (I- 
A'') are expressed in T2 by transfection, the cell 
line is unable to process internalized protein an- 
tigens into class II MHC-associated peptides rec- 
ognizable by T cells. To date, it appears that both 
mouse and human class II molecules expressed in 
T2 associate normally with the invariant chain 
and are transported to an endosomal compart- 
ment where the invariant chain is proteolytically 
cleaved. The missing steps in generating func- 
tional class II MHC-peptide complexes remain to 
be determined, but again appear to be the proper- 
ties of MHC-linked genes. 
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