Intracellular self/not-self discrimination

FORSDYKE at QUCDN.QueensU.CA FORSDYKE at QUCDN.QueensU.CA
Wed Mar 2 14:13:06 EST 1994


THE NEED FOR INTRACELLULAR SELF/NOT-SELF DISCRIMINATION

The maturation of immunologically competent cells involves the deletion
or inactivation of cells which react with high specificity with self antigenic
determinants. Since the cells first "show their colours" by displaying
antigen-specific, outward-facing, receptors at their surfaces, their
"education" is regarded as part of an extracellular process of self/not-self
discrimination. A cell whose receptors happen to react with some free or
cell-borne self-antigenic determinant will either be deleted or inactivated.

   The principle of intracellular self/not-self discrimination was firmly
established with the discovery of bacterial restriction/modification
systems. An advantage to higher multicellular organism of having an
intracellular self/not-self discrimination system became particularly
apparent with the finding that peptides from both self and foreign
intracellular proteins can be displayed at the cell surface in association
with major histocompatibility complex (MHC) proteins; here they are
recognized by immunologically competent cells of the cytotoxic T cell
class. 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".

  In the absence of such a sorting mechanism, an organism would depend
solely on prior education of T cells to prevent their being activated by
self-peptide-MHC complexes. Several studies indicate that this deletion
of potential self-reacting T cells would create numerous gaps in the T cell
repertoire, which might adversely affect resistance to infection
For example, Du Pasquier and coworkers (1977) presented
evidence that polyploid toad species, while apparently functionally
polyploid for most genes, are functionally DIPLOID for MHC genes. That
this had occurred over evolutionary time was suggested by the
observation that healthy laboratory-made polyploid toads expressed all
MHC loci. 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 so that the
modern polyploid survivors would be MHC diploid. As Vidovic and
Matzinger (1988) succinctly state: "There will be a selective pressure
against the expression of too many MHC genes. Because the number of
cells in the immune system is finite, the elimination of cells recognizing
self obviously reduces the recognition repertoire of the individual."

  The prior sorting of peptides intracellularly would mean that populations
of T cells would exist with the potential to respond against self-peptides
should they be inadvertantly, or artificially, presented. Thus, Schild and
coworkers (1990) found that cytotoxic T lymphocytes "are only tolerant of
those endogenous self peptide sequences that are presented by MHC
Class I-positive cells in a physiological manner".

  For a possible mechanism of intracellular self/not self discrimination see
Forsdyke, 1994.

REFS:

Du Pasquier et al. (1977) Immunogenetics 5, 129-147. The genetic control of
   histocompatibility reactions in natural and laboratory-made polyploid
   individuals of the clawed toad Xenopus.
Forsdyke, D. R. (1994) J. Biol. Systems (in press) Entropy-driven protein
   self-aggregation as the basis for self/not-self discrimination in the
   crowded cytosol.
Hedrick, S. M. (1992) Cell 70, 177-180. Dawn of the hunt for non-classical
   MHC function.
Schild et al. (1990) Science 247, 1587-89. Limit of T cell tolerance to self
   proteins by peptide presentation.
Vidovik, D. & Matzinger, P. (1988) Nature 336, 22-225. Unresponsiveness to
   a foreign antigen can be caused by self-tolerance.

                      Sincerely, Don Forsdyke, Discussion Leader,
                                               Bionet Immunology



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