Organization: Queen's University at Kingston
Date: Monday, 17 Aug 1992 17:57:00 EDT
From: <FORSDYKE@QUCDN.QueensU.CA>
Newsgroups: bionet.immunology
Subject: Re: Journal Watch: MHC and intracellular self
 <1992Aug14.151645.4343@news2.cis.umn.edu>

In article <1992Aug14.151645.4343@news2.cis.umn.edu>, shiv@tsp.med.umn.edu (Shiv
Prasad) says:
>
>In article <92225.094723FORSDYKE@QUCDN.QueensU.CA> <FORSDYKE@QUCDN.QueensU.CA>
>writes concerning the article:

>>Journal Watch. "Dawn of the Hunt for Nonclassical MHC Function" by
>>Stephen M. Hedrick. Cell vol 70, p. 177-180. 24th July 1992.
>>Quotes Hedrick:
>>Perhaps there is a mechanism that could help to sort peptides into those
>>originating from self and those originating from foreign proteins."
>> Comments on the Hedrick quotation:
>>   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.
>>
>>    Sincerely,  Don Forsdyke
>
> Prasad replies:

>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.
>
>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.

Forsdyke replies:

  Thank you for your exposition of the conventional wisdom on T cell
education. There are still some problems, as you are aware. The alterna-
tive view, that there IS an intracellular mechanism for self/not-self
discrimination, is not refuted by the finding of some "self" peptides
in cell surface MHC complexes, although my arguments would perhaps have
met less resistance if all extracted peptides had been "not-self".

  I do not envision that the intracellular mechanism would occur at the
level of MHC binding or at the level of the peptide-transporter.It occurs
at the level of deciding WHICH cytosolic molecules to subject to peptide
cleavage (we are talking about MHC Class I presentation here).

  Start, by forgetting about cells and imagine placing a set of "self"
cytosolic proteins in a test tube (A,B,C,D,E,F,G,H). Now add a not-self
protein (X). The problem is to find a way of specifically selecting X for
degradation. Double the concentration of all the proteins. Nothing
happens. Double again, and again. Something is now happening. One of the
proteins is aggregating. It is doing this specifically, self with self.
The mechanism for this is set out in Lauffer's book "Entropy-driven
Processes in Biology (Springer. 1975). Now, as we have it set up,
there is no particular reason for any one protein to be the first to
aggregate. It could be one of A to H. It could be X. But once it has
aggregated, it has marked itself as different. As such, it might be
recognized by a specific proteolytic complex (proteosome?) and some of
its peptides made available for coupling to MHC protein.

  So, now we need to think about conditions needed to ensure that X is
the first to aggregate, not A to H. Scratch your head a little, and let
me know what you come up with!
                          Sincerely,
                               Don Forsdyke, Department of Biochemistry,
                                             Queen's University, Kingston
                                             Canada.
References:
Forsdyke, D.R. (1992) Bionet.immunology 814, 947edt
Prasad, S. (1992) Bionet.immunology 812, 1516gmt