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...
>>Derek Gray <derek.gray at surgery.oxford.ac.uk>
>>Derek: Thanks for the comments regarding allograft rejection. Is there
>an easily obtained citation for the observation that in allograft
>rejection, the antigen carried by the MHC is irrelevant? From a
>theoretical perspective, it still seems rather contradictory that MHC
>retriction (ie., lack of 'response' due to MHC pleomorphism) and
>allograft rejection (ie., 'awesome response' due to MHC pleomorphism)
>should be used to explain one-another.
It is not true that the peptide is "irrelevant" in allograft rejection - the
tremendous response is due to cross-reactivity of many T cells with the
foreign MHC+peptide. The individual TCR's recognize specific peptide/MHC
complexes (see Malarkannan et al., Journal of Immunology 157:4464-4473).
>Ian York <iayork at panix.com>>Ian: Thanks for your comments regarding crystal structures, I will
>certainly check out the articles to which you referred (although I do
>have that Garcia clip-out which includes Wilson as the senior author).
>In that Garcia article, the authors conclude that CDR3 of both the alpha
>chain and the beta chain of the TCR contact peptide alone. They note
>that CDR3 is the most variable hypervariable domain of the TCR (and I
>attach significance to that). The authors also conclude that CDR1 and
>CDR2 of both chains contacts both peptide and MHC alpha helical domains.
>As you know, the alpha helical regions of the MHC are rather limited in
>their allelic variability (most pleomorphism occurs where the TCR should
>not see it that easily -- the beta-sheet floor, especially near the
>specificity pockets). So, my thought is this: how can allelic
>variability (pleomorphism) lead to MHC restriction most easily? My
>answer would be by determinant selection rather than MHC
>recognition......
It is true that the peptide is the most variable part of the peptide/MHC
complex, but very little of that variability is visible to the TCR - at most
3 or 4 residues - so most of the binding energy probably *does* come from
TCR-MHC interactions. Also, although the *sequence* of the alpha helices may
not vary much, the *structure* is likely to be altered, if subtly, by the
identity of the peptide bound in the groove - thus, the TCR is truly seeing
the complex, rather than either component individually.
>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.
Ken Frauwirth
--
Ken Frauwirth (MiSTie #33025) _ _
frauwirt at mendel.berkeley.edu |_) * |/ (_ |\ |
http://www.ocf.berkeley.edu/~frauwirt/ |_) | () |\ (_ | \|
DNRC Title: Chairman of Joint Commission on In-duh-vidual Affairs
