Self/Not-self discrimination (YORK)

Dr M.R. Clark mrc7 at cus.cam.ac.uk
Fri Aug 19 06:28:28 EST 1994


In article <94230.085718FORSDYKE at QUCDN.QueensU.CA>,
 <FORSDYKE at QUCDN.QueensU.CA> wrote:
>In article <32ttqj$13o at nermal.cs.uoguelph.ca>, gappleya at uoguelph.ca (Greg
>Appleyard) says:
>>
>>My question is, since T-cells do the self/non-self discrimination and
>>such discrimination is made vigilent against intracellular infections
>>through thymic education, how is it that self-specific T-cells exist
>>normally in the periphery without rampant autoimmunity. The self-specific
>>T-cells must be regulated, but how? It seems a paradox that self/non-self
>>discrimination is made on the basis of selecting T-cells without
>>self-reactivity (negative selection) and yet self-specific T-cells are
>>part of the normal lymphocyte repertoire.
>
>      No paradox. Self-specific T-cells are part of the normal lymphocyte
>      repertoire because peptides from the corresponding intracellular self
>      proteins have not been presented in order to cause the deletion of the
>      self-specific T-cell clones. This is because there is an intracellular
>      mechanism  for distinguishing self/not self. This mechanism is very
>      "primitive" in that it evolved before multicellular organisms evolved.
>      (J.Th.Biol. 167,7-12; J. Biol.Sys.2, in press). Some self peptides are
>      presented, and in these cases T cell deletion has occurred.
>
>                      Sincerely, Don Forsdyke Discussion Leader
>                                              Bionet.immunology
There is absolutely no need to invoke a mechanism for APCs to discriminate
self from non-self peptides. Which peptides are presented may indeed be
influenced by their sequence, concentration , degree of agregation and
for MHC Class II presence in an immune complex with Antibody and or complement.
However whether a given peptide chosen at random will be presented by MHC class
I on an APC is in no way dependent on whether it derives from a self or a no
non-self protein. The key feature is that T-cells as individuals and also
as co-operating groups go through a stage during maturation where if they
they see antigen they learn not to react in a hostile fashion. ie they
become anergic, tolerant or are deleted. Some important new findings which
in part relate to the classical ideas of suppression is that once you have a 
significant population of cells which are tolerant of self they can then
"teach" other cells to be tolerant. I refer to the recent work from
Herman Waldmann's group in particular from Shixin Qin and the discussions
of infectious tolerance.
It is perfectly OK to present self peptide, it happens in all individuals.
The discrimination is carried on by the T-cells which learn sef during
development. Occassionaly the system breaks down and autoimmunity
occurs but this is not the "common state". In fact the most remarkable
thing about the immune system is that it manages to make any kind of
response at all! If you ever try and immunise an animal with a foreign
protein you will realise just how difficult it is in most cases.
Immunologists have to employ all kinds of tricks to make the  protein
immunogenic despite the fact that it is foreign, it is antigenic
and peptides from it can be presented to T-cells. On the whole
the immune system tends to default to unreactivity which is why
vaccine development is so complex! :)
Please note I am off on vacation for three weeks so if you
reply to this I may not respond for a while.


    _              
  o/ \\    //            ||  ,_ o   Mike Clark, mrc7 at cus.cam.ac.uk
 <\__,\\  //   __o       || /  /\,  Cambridge University, Dept. Pathology
  ">    ||   _`\<,_    //  \\ \> |  "an antibody engineer who prefers the
   `    ||  (_)/ (_)  //    \\ \_   mountains"
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