Intracellular self/not-self discrimination

Thu Mar 17 17:42:52 EST 1994

It's been two weeks since Dr. Forsdyke posted this message, and
unfortunately, I haven't seen any comments on it (although I do
occassionally miss some of the posted items).  So, since we've been
discussing the item here, I'll throw out a few of our objections.
Mind you, they are not objections to the possibility of intracellular
self/not-self discrimination, but arguments against the need for it.

Forsdyke writes:
> Since the final T cell repertoire reflects the processes of
> negative and positive selection, every additional functional MHC
> gene would increase the number of potential anti-self T cells which
> would have to be deleted (negative selection). This would decrease
> the range of foreign proteins to which the surviving positively
> selected cells could respond. Fitness would be impaired. Individuals
> which lost excess MHC loci through mutation, would then have a
> selective advantage ...

I agree with his interpretation of the effect of increased MHC
expression on negative selection, but he seems to have ignored the
effect on positive selection.  Since the vast majority of T cells are
neither positively nor negatively selected (99%), the newly-selected
thymocytes (positive or negative) would be primarily from the pool of
cells which previously had been non-selected.  Increased MHC-peptide
combinations in thymic development would be more effective in
increasing the number of positively selected thymocytes from the large
non-selected pool than increasing the number of negatively selected
thymocytes from the small positively-selected pool.

With this in mind, the reason for a limitted set of MHC might be to
maximize antigenic responsiveness while keeping the potential for
*peripheral* development of autoreactivity (as a product of rare TCR
mutation) at a minimum.

> In the absence of a mechanism for distinguishing intracellularly
> self peptides or proteins from foreign (e.g. virally-derived)
> peptides or proteins, cells would have to display all MHC-bound
> peptides.  Hedrick (1992) has noted that "It is hard to understand
> how peptides derived from foreign antigens can compete with the tide
> of self peptides...", and has suggested that "Perhaps there is a
> mechanism that could help to sort peptides into those originating
> from self and those originating from foreign peptides".

To begin with, this is much more of a problem for Class I, presenting
intracellular antigens (self-antigens being produced on a constant
basis), than Class II, presenting phagocytized extracellular antigens.
However, even this might not be a problem, if one considers the
differential production of foreign antigens versus self antigens
during something like viral infection or bacterial phagocytosis.  In
both situations, I would expect a majority of the MHC (Class I and II,
respectively) to be presenting foreign antigenic peptides.

Even in situations of low antigen concentrations, it has been
estimated that only 50-300 TCR must be engaged with MHC-peptide to
trigger a full T cell response.  Considering 10^4-10^5 TCR per T cell
and 10^5-10^7 MHC per APC, all of the above arguements might be moot,
since very few of the MHC even need to have foreign antigen peptides
to effect a T cell response.

Dean Lee                        * We dance 'round in a ring         *
Dept of Micro and Mol Genetics  * and suppose,                      *
Loma Linda University           * But the secret sits in the middle *
dLee at ccmail.llu.edu             * and knows.               R. Frost *

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