Recognition of self vs non-self by macrophages?

Ian A. York york at mbcrr.dfci.harvard.edu
Mon Nov 7 13:07:41 EST 1994


In article <9411071626.AA06916 at xtal220.harvard.edu> collins%xtal220 at HARVARD.HARVARD.EDU writes:
>
>	I believe that B7 would not be upregulated when self-
>peptide is present in the MHC, because there would be no primary signal. This
>would be regardless of the presenting cell type, macrophages or whatever. 
>There would be no recognition by a TCR of a MHC/self-peptide because that 
>population of T cells that would recognize the self-peptide has been 
>anergized or deleted from the repetoire during development in the thymus.
>I think your question has two phases, 1. How do macrophages recognize mutated
>or foreign material? and 2. How is the signal propogated to the humoral 
>response system? The first question, I can't answer. The second would be 
>through the normal signal pathways through MHC antigens. I don't believe 
>anyone has shown that self-peptides are recognized by TCR but then the 
>differentiation of self vs non-self takes place at the level of second 
>messengers. 

I'm not sure what you are trying to say here.  What do you mean by a 
"primary signal"?  As far as I know, the presence or absence of a peptide 
in the MHC (self or foreign) has nothing to do with the upregulation of 
B7.  The upregulation occurs becase of the association between MHC and 
TcR - presmably, but not necessarily, becase of cross-linking of the 
MHC.  Now becase the TcR usally recognize only MHC with peptide - and 
particularly MHC with foreign peptide - it _looks_ as if foreign peptide 
is necessary to upregulate B7; but in principle empty MHC could do it as 
well, if the empty MHC would interact with TcR.  I believe a similar 
experiment has been done, using superantigen to trigger the interaction 
with TcR.  
	Your comment about the non-recognition of self-peptide is to the 
point, although of course there can be some self-reactive TcR's sneaking 
through (and if these are not anergized they can reslt in atoimmune 
disease).  
	You say "How do macrophages recognize mutated or foreign material?"
and the answer is they don't . . . I keep saying this, but it bears 
repeating.  You also say "How is the signal propogated to the humoral
response system?"  -  I'm not sure how this applies to the original question.
	A nmber of groups have shown that self-peptide can be recognized 
by the TcR.  Here are some references you may find interesting:

      Immunogenicity and tolerogenicity of self-major histocompatibility
      complex peptides.   
      Benichou G et al.
      Journal of Experimental Medicine.  172(5):1341-6, 1990

      Limit of T cell tolerance to self proteins by peptide presentation.
      Schild H.  Rotzschke O.  Kalbacher H.  Rammensee HG.
      Science.  247(4950):1587-9, 1990

      Peptide recognition, T cell receptor usage and HLA restriction
      elements of  human heat-shock protein (hsp) 60 and mycobacterial 65-kDa
      hsp-reactive T cell clones from rheumatoid synovial fluid.
      Quayle AJ et al
      European Journal of Immunology.  22(5):1315-22, 1992

      MHC class II molecules bind indiscriminately self and non-self peptide
      homologs: effect on the immunogenicity of non-self peptides.   
      Sette A et al
      International Immunology.  5(6):631-8, 1993


For an interesting hypothesis (with which I do not entirely agree, but 
hey, what do I know anyway) see - 

      How cytotoxic T cells manage to discriminate nonself from self at the
      nonapeptide level.   
      Ohno S.
      PNAS 89(10):4643-7, 1992




Ian


-- 
Ian York   (york at mbcrr.harvard.edu)
Dana-Farber Cancer Institute, 44 Binney St., Boston MA 02115
Phone (617)-632-4328     Fax  (617)-632-2627




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