MHC restriction

Jorg Kirberg kirberg at nki.nl
Sat Mar 1 06:06:33 EST 1997


In article <3316041F.2451 at ucla.edu>, Ken Miyasaki <kmiyasak at ucla.edu> wrote:

> I was just curious as to how immunologists viewed "MHC restriction."
> Does it really exist? Isn't it just a laboratory artifact (based upon
> measurement of secondary immune responses)? Doesn't the TCR see mainly
> the antigen and not the MHC (with greater than three orders of magnitude
> difference in affinity). So why was the 1996 Nobel Prize awarded to
> people who proposed this dual cognition stuff?

Dear Ken,
while all other replies were mainly concerned about the way the TCR
binds MHC/peptide they did not at all adress your good point of whether 
the MHC restriction as observed in those old Zinkernagel and Doherty
papers is just a laboratory artifact based on the preferential outgrowth
of cells that were specific for the antigen/MHC combination they tested
for. (Sorry, no time to shorten this sentence).
However, this has been clarified (much later actually) by using TCR
transgenic animals (apart from a few other approaches). In these animals
a given TCR will only end up on mature peripheral T cells if the TCR
was able to bind to the selecting MHC molecules on thymic epithelial cells.
These data showed that it is not a preferential outgrowth of cells
that just happen to have the right specificity but only cells will
mature that have the right MHC restriction - and all this happens in
the absence of the antigen (peptide).
Just have a look at the following papers:
Kisielow, P, Teh, HS, Blüthmann, H and von Boehmer, H. "Positive selection
of antigen-specific T cells in thymus by restricting MHC molecules".
Nature 335 (1988): 730-3.
Sha, WC, Nelson, CA, Newberry, RD, Kranz, DM, Russell, JH and Loh, DY.
"Positive and negative selection of an antigen receptor on T cells in
transgenic mice". Nature 336 (1988): 73-6.
Berg, LJ, Pullen, AM, Fazekas, dSGB, Mathis, D, Benoist, C and Davis, MM.
"Antigen/MHC-specific T cells are preferentially exported from the thymus
in the presence of their MHC ligand". Cell 58 (1989): 1035-46.
Scott, B, Blüthmann, H, Teh, HS and von Boehmer, H. "The generation of
mature T cells requires interaction of the alpha beta T-cell receptor with
major histocompatibility antigens". Nature 338 (1989): 591-3.

In addition, it has been shown that positive selection - which 'imprints'
MHC restriction in the T cell population - happens in the absence of
cell division:
Huesmann, M, Scott, B, Kisielow, P and von Boehmer, H. "Kinetics and
efficacy of positive selection in the thymus of normal and T cell receptor
transgenic mice". Cell 66 (1991): 533-40.

'Mechanistically', T cells fix the ongoing TCRa chain rearrangements only
if the TCR will bind to the MHC; this is detectable by a reduced RAG gene
expession:
Borgulya, P, Kishi, H, Uematsu, Y and von Boehmer, H. "Exclusion and
inclusion of alpha and beta T cell receptor alleles". Cell 69 (1992):
529-37.
Brändle, D, Müller, C, Rülicke, T, Hengartner, H and Pircher, H.
"Engagement of the T-cell receptor during positive selection in the thymus
down-regulates RAG-1 expression". Proc Natl Acad Sci U S A 89 (1992):
9529-33.
Petrie, HT, Livak, F, Schatz, DG, Strasser, A, Crispe, IN and Shortman, K.
"Multiple rearrangements in T cell receptor alpha chain genes maximize the
production of useful thymocytes". J Exp Med 178 (1993a): 615-22.

In the end, it is quite fine to give (finally) a nobel prize to those that
showed the importance of the MHC in the T cells' specificity. However,
their initial data were not at all aimed at showing how the MHC restriction is
                                                   ^^^^^* (see below)
'imprinted' in the T cell repertoire and this was for long time a field where
 much dispute was ongoing. Even quite recently there were still proponents
^^^^^^
that doubted positive selection (Matzinger, P. (1993). Why positive
selection? Immunol Rev, 135, 81-117.) (though some of her arguments were
already
disproven by available data; my comment).



* of course they showed that the thymus was apparently responsible:
Zinkernagel, R. M., Callahan, G. N., Althage, A., Cooper, S., Klein, P. A.
and Klein, J. (1978). On the thymus in the differentiation of "H-2
self-recognition" by T cells: evidence for dual recognition? J Exp Med,
147, 882-96.

but this still could not rule out your point of preferential expansion.
See therefore also:
Matzinger, P and Mirkwood, G. "In a fully H-2 incompatible chimera, T
cells of donor origin can respond to minor histocompatibility antigens in
association with either donor or host H-2 type". J Exp Med 148 (1978):
84-92.
Zinkernagel, RM, Althage, A, Waterfield, E, Kindred, B, Welsh, RM,
Callahan, G and Pincetl, P. "Restriction specificities, alloreactivity,
and allotolerance expressed by T cells from nude mice reconstituted with
H-2-compatible or -incompatible thymus grafts". J Exp Med 151 (1980):
376-99.

where the latter experiments rather concluded that the thymus as organ
itself was required irrespective of its MHC genotype. (This is all a real
mess to read but shows why I said MUCH dispute).


Lot's of reading but have fun,
jorg


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Joerg Kirberg                              Tel. 0031 - 20 - 512 19 98
The Netherlands Cancer Institute           FAX  0031 - 20 - 512 20 11
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