Self/nonself discrimination

Ken Frauwirth BioKen frauwirt at mendel.Berkeley.EDU
Fri Aug 12 00:16:19 EST 1994

In article <CuE151.K4L at>, shiv at (Shiv A. Prasad (MicroBio)) writes:
|> The experiment to do would be to use 2 mouse strains that are identical
|> except for one allelic forms of one gene.  Hemoglobin would not be a good
|> choice since it's extracellular.  MHC is also a poor choice as it's on the
|> cell surface, we need an entirely intracellular protein, call it protein X.
|> In both strains, protein X (a or b allele) has evolved to the "proper" 
|> intracellular concentration as determined by Don's hypothesis. So there would
|> be no "intracellular nonself."   Protein X should also have MHC- binding 
|> motifs. Now transplant an organ from strain a to strain b.  If the graft is 
|> rejected by immunological mechanisms (T cell response to the foreign allele), 
|> then it is highly unlikely that intracellular self-nonself discrimination had 
|> anything to do withthe rejection. If the graft is accepted, and, in no
|> system can an immune response to the foreign allele be demonstrated, then
|> Don's hypothesis survives a challenge.  One problem with this experiment is
|> the need for costimulation by Target cells of the graft.  If tolerance happens
|> to be due to anergy or ignorance, no conclusion on intracellular 
|> discrimination can be reached. 
|> Of course all the controls have beenleft out of this "gedanken" experiment, 
|> but you get the point.
|> I am almost certain that someone has though of this and done the experiment.
|> Shiv 
|> shiv at

Although I don't know if this *exact* experiment has been done (it is
difficult to find intracellular polymorphisms), a similar experiment
*has* been done - about 50 years ago.  It is known that female mice will
reject skin grafts from male mice of the same strain, although the male
mice will accept grafts from the females.  This is presumably due to
expression of male-specific genes (either Y-linked, or regulated by
Y-linked genes).  Unfortunately, no "H-Y" antigen, as they are
known, has been isolated, so it is not known if the proteins are actually 
intracellular (it is hypothesized that some may be transcription factors). 
However, the H-Y response *is* restricted by MHC Class I, so it seems to
fit the bill, indicating that intracellular self-peptides really are
presented on Class I MHC (and research supports the idea that the protein
is expressed at a low level, so aggregation is likely not a factor).

Similarly, the bm mutations in Class I molecules also support this idea. 
Some of these mutations are point mutations or very small substitutions
in the floor of the peptide-binding cleft (K-bm1, for example, is different
from K-b only at 3 residues in the cleft).  These residues are proposed
to interact with the peptide, but *not* with the TCR, yet a strong allo
response can be generated between H-2b and H-2bm1, suggesting that the
peptides displayed on the MHC are different.  Although it is possible
that these peptides could be derived from extracellular antigens,
research in our lab indicates that at least one comes from an internal

Ken Frauwirth (MiSTie #33025)  _           _
frauwirt at  |_) *    |/ (_ |\ |
Dept. of Molec. & Cell Bio.   |_) | () |\ (_ | \|  
Univ. of Cal., Berkeley   .sig made under strict rabbinical supervision

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