Self/Not-self discrimination (YORK)

Paul J Travers p_travers at icrf.icnet.uk
Mon Aug 15 07:49:36 EST 1994


In general terms I would agree with the points that Ian York has made, but
would like to extend the argument a little further.  

  Ian comments
"The somatic cells simply present a representative sample of just about
everything that's going on in their cytoplasm and let the T cells worry
about sorting out what belongs and what doesn't.  That's why thymic
education is so elaborate."

  I would like to suggest that the situation is a little more complicated
than that, although the basic notion is, I think, correct.  Recent data has
suggested that the specificity of the proteasome is affected by the
inclusion of the MHC encoded components, the LMP's.  Interferon stimulation
(and any other stimuli that induce the LMP's) will therefore change the
nature of "self" (and "non-self"), as seen by T cells.  Now, it seems
sensible to me that the "self" to which we should be tolerant, should be
the "activated" self, and that non-responsiveness to "resting" self is
mediated either by the overlap between the two repertoires or by clonal
ignorance (remembering that resting levels of class I are also low, and are
upregulated by the same stimuli that upregulate the LMP's).  I am told that
LMP's are constitutively expressed in the thymus (sorry, my informant
couldn't say anything about cell type in the thymus - it was a whole thymus
Northern), which may be consistent with this notion.

	The distinction between resting and activated self may not be restricted
to class I molecules.  Now that DM/H2-M appears  to play an essential role
in antigen interactions with class II molecules, upregulation of DM in
APC's may also change the nature of the perceived "self".  

	Secondly, the immune system responds to a series of non-specific signals
that inform the system that an infection is present and prime the response
- for bacterial infections these are the responses to cell wall components
such as mannans, lipopolysaccharides etc. These have a number of effects,
including the activation of costimulator expression on potential antigen
presenting cells, rendering them effective stimulators of naive T cells. 
For viral infections, the "priming" component may be the activation of NK
cells and their subsequent production of interferon.  In both cases it
appears that nonspecific (in the Burnett sense of using non-clonally
distributed receptors) response mechanisms act to upregulate antigen
presentation and potentially to alter the antigenic repertoire.

	It is my expectation that these non-clonal mechanisms will predate the
adaptive immune system, and thus the self/non-self discrimination
mechanisms required by the adaptive immune system will have evolved against
a background in which both the activation of the immune system and the
definition of self are conditioned by the presence of pathogens.

                               Paul
-- 
Paul J Travers                          phone : +44-(0)71-631-6862 (office)
ICRF Structural Biology Unit             "       "       "    6868 (lab)
Birkbeck College                          fax : +44-(0)71-631-6803
Malet Street
London WC1E 7HX                         email :  p_travers at icrf.icnet.uk
England                                    or :  paul at histo.cryst.bbk.ac.uk



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