Self/nonself discrimination

Shiv A. Prasad MicroBio shiv at
Sun Jul 17 10:04:09 EST 1994

In article <308fu0INNcre at> ejf at (Ephraim Fuchs) writes:
>One of the cardinal features of the immune system is its ability to 
>discriminate self from nonself.  Recent experimental evidence suggests 
>that a two signal model of lymphocyte activation is the biological basis 
>for S/NS discrimination.  For CD4+ T cells, signal two is delivered by 
>the antigen presenting cell.

Clonal deletion in the thymus may play the major role in self-nonself 
discrimination by limiting the number of potentially autoreactive T cells 
that are exported to the periphery.  

>Here is the question:
>Since antigen presenting cells take in antigens randomly from their 
>environment, how is their delivery of signal two regulated so as to 
>achieve a self/nonself discrimination?

I guess any answer to this would be a load of speculation, so here goes.
I would argue that circulating self Ag would comprise most of the randomly
endocytosed Ag.  As they are circulating, they might well be present in the
thymus to induce deletion of high-affinity cognate T cells.  The Ag of
concern are tissue-specific ones not present in the thymus, or Ag expressed
late in development, after most of the T cell repertoire has been selected.
For the former, they might be abberently presented on class II+ APC that
lack costimulatory ability (non-professional APC).  These could potentially
induce anergy in autoreactive T cells.

For other Ag, costimulation could require an inflammatory milleu (Janeway's
"natural adjuvant" hypothesis).  In the absence of this T cells might
encounter Ag on costimulation-deficient APC and become anergic.

And of course, "Other Factors": the presence of self-Ag in immunosuppressive
milleus, e.g. the anterior chamber of the eye (ACAID); suppression (excuse me, 
immunoregulation as it's now called); clonal ignorance which could account for
the lack of response by low-affinity, autoreactive T cells.

In the 1993 Ann Rev. Immunol, JFAP Miller has a rather nice review on
peripheral tolerance.

Shiv A. Prasad				shiv at
Department of Microbiology		Lab: (612) 626-0773
University of Minnesota			FAX: (612) 626-0781
Box 196 UMHC				
Minneapolis, MN 55455

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