In article <92225.094723FORSDYKE at QUCDN.QueensU.CA> <FORSDYKE at QUCDN.QueensU.CA> writes:
>Journal Watch. "Dawn of the Hunt for Nonclassical MHC Function" by
>Stephen M. Hedrick. Cell vol 70, p. 177-180. 24th July 1992.
>>Perhaps there is a mechanism that could help to sort peptides into those
>originating from self and those originating from foreign proteins."
>> Having been pushing such a mechanism for some time (J.Theoret.Biol.
>vol 115, 471-473. 1985), I was pleased that at least the possibility of
>the existence of such a mechanism was being acknowledged. However, my
>> Sincerely, Don Forsdyke
It seems that self-nonself discrimination at the level of peptide-MHC
binding would add another (unnecessary?) level of complexity to the immune
system. We all know how specificity is governed by T cell selection, and
the question of tolerance to extra-thymic self Ag can be explained by
clonal anergy, or perhaps even suppression. I find it difficult however
to envision the MHC molecules, or some other component of presentation,
as discriminating between self and nonself.
It is becoming more apparent that there are common motifs in peptides that
bind certain MHC molecules, and these motifs appear to be present in both
the self and nonself peptides that have been eluted and sequenced from MHC.
Therefore binding still appears to be somewhat promiscuous, and this makes
sense (that MHC-peptide binding doesn't discriminate) or else thymic selection
wouldn't be what it is. However it seems that you suggest discrimination at
the peptide-transporter level. Let's use thymic selection as a model for
analyzing this.
Self-peptides are presented by thymic APC, allowing the deletion of autorx
thymocytes. Hence in these APC self-peptides would be bound and transported
by the intracellular complex. At this point we are unable to determine what
would happen to a non-self peptide, until we look at neonatal tolerance
experiments. Presumeably in these models the foreign Ag is transported to
the thymus by the blood and then is processed, presented, and the resulting
Ag-MHC complexes can delete thymocytes with cognate receptors. The same
processing events occur with the injected peptide as with the self-peptides
(again a presumption, but with little evidence to think otherwise). So it
appears that the thymic APC cannot discriminate between self and non-self
peptides.
If ONLY foreign peptides were expressed in conjunction with MHC on the cell
surface, that would be more efficient. But we know from the peptide elution
experiments that this doesn't occur. Therfore it is logical for the APC
to express "every" peptide capable of binding MHC, and letting the T cell
determine what is self and what is foreign.
Shiv
shiv at lenti.med.umn.edu
P.S.
Don, I could have read your J. Theor. Biol. paper, but that wouldn't make
for an interactive net-discussion.
