In article <5ffu0r$rnk at agate.berkeley.edu>,
frauwirt at notmendel.Berkeley.EDU (Ken Frauwirth (BioKen)) wrote:
> In article <331B2EE0.6206 at ucla.edu>, Ken Miyasaki <kmiyasak at ucla.edu> wrote:
> >I just wanted to thank everyone for their thoughtful comments. I still
> >need to do some reading, but at least I have a feel for what
> >immunologists think, which is important to me. I have some responses,
> >below, and again, would appreciate any corrections or other feedback...
> >
[Snip]
> >Joerg: Clearly, I need to read those papers! Especially Matzinger...
> >Thanks!!!!! (Especially about how anything happens in the absence of
> >antigen... Since MHC molecules are always loaded with something at 37°
> >C, I need to see whether or not I believe those papers you cite).
>> Be wary of anyone who talks about "empty" MHC molecules. To my knowledge,
> nobody has physically demonstrated that *any* cell surface MHC molecules
> are truly empty. People rely on indirect assays (instability, ease of
> loading exogenous peptide, lack of certain antibody epitopes) as evidence of
> empty MHC molecules, but these do not preclude the presence of low-affinity
> peptides, for example. I realize it is difficult to directly prove emptiness
> (the closest would probably be to try to acid-elute peptides from presumptive
> empty molecules, but even that would rely on a negative result), but it has
> been shown with Class II MHC that there are peptides (the invariant-chain-
> derived CLIP, for example) which can bind without conferring "peptide-bound"
> traits to the MHC molecules.
Dear both Ken's,
just to avoit getting stuffed in the wrong bag: the papers I cited have
really nothing to do with empty MHC molecules; they were before that time.
What they simply showed is that MHC restriction is 'imprinted' into the
T cell repertoire (because TCR transgenic cells could not make it towards
mature cells in a nonselecting=allogenic MHC background). This proved
that MHC restriction (as observed in experimental systems) is a consequence
of T cell development in the thymus and not due to preferential outgrowth
of cells.
And it is right that at least the major part (if not almost 100 %) of the
MHC molecules is loaded with peptide - most of the time these will be derived
from self proteins. Therefore my statement that T cell selection is achived
in the absence of the <nominal> peptide (the one the T cell will later be
responding to if presented on the right MHC).
While the nominal peptide, the T cell will be specific for, is not there in big
quantities (otherwise it would result in negative selection: ellimination
of those T cells) there is one author whom proposed there might be
minute quantities due to errors in the transcription/translation machinery
(I think it was Kourilsky from Paris) - but maybe discussing even this goes
a bit far regarding the original topic.
[Of course, there are now several studies showing that small doses of
the nominal peptide (or a similar one, sometimes being an antagonist)
could actually enhance positive selection in systems
where these peptides could easyly be loaded by giving them exogenously -
because a substantial fraction of the MHC molecules is empty. However,
though this is interesting in the light how the enourmous T cell
repertoire is shaped it is the prolongation of it's basis: T cells
have a MHC restriction that is 'imprinted' during developent in the
thymus. T cells that could not make any receptor or one that does not bind
to the individuals own MHC molecules will die in the thymus.]
And please, read the Matzinger paper as the last one: She will cite the others
anyhow and it is good to have the knowledge of those.
jorg
---------------------------------------------------------------------
Joerg Kirberg Tel. 0031 - 20 - 512 19 98
The Netherlands Cancer Institute FAX 0031 - 20 - 512 20 11
Div. Molecular Genetics (H4) E_mail kirberg at nki.nl
Plesmanlaan 121
NL - 1066 CX Amsterdam
The Netherlands
