Journal Watch: MHC and intracellular self

Shiv Prasad shiv at tsp.med.umn.edu
Mon Aug 17 20:33:06 EST 1992


In article <92230.175700FORSDYKE at QUCDN.QueensU.CA> <FORSDYKE at QUCDN.QueensU.CA> writes:

>  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.
>
>                          Sincerely,
>                               Don Forsdyke, Department of Biochemistry,
>                                             Queen's University, Kingston
>                                             Canada.

In your experiment it would seem that whichever protein aggregates first
would depend on the initial concentration of each protein, and the homotypic
affinities.  A situatioon in which the non-self would be in excess (to move
this back into the cell) is a viral infection, where certain viral proteins
are made far in excess of the cellular proteins.  If the viral proteins are
more quickly degraded by proteolytic complexes, this may be a simple question
of availability and competition.  For this cell to be recognized as a target
the infecting virus must not lyse the cell.  So we are left to ponder viruses
that make a large quantity of their own proteins while not being lytic.  My
knowledge of viruses doesn't include this information however.

Going back to the cell-free scenario (i.e. this just popped into my mind)
the viral proteins may be in excess of the cellular proteins, and they may
also aggregate more easily, since an aggregate of one protein often forms
a viral capsid.  So I can see there where X would aggregate before A-H.
But again, recognition of this non-self aggregate would be the proteolytic
complex binding to the aggregate that is more in abundance.  This form of
discrimination would be (through my T cell eyes) a rather loose useage
of the term self-nonself discrimination.  For example if two or more
foreign protein were present, let's say the capsid protein and the viral
polymerase (packaged at low numbers per virion), the capsid protein would
outcompete the self proteins and the polymerase.  The polymerase would not
necessarily outcompete the self-proteins, as it may not be present in large
enough quantities to aggregate before the self molecules do.

Is this close to the point that you're trying to make?

Shiv



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