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Exogenous
MHC Class II
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The
MHC Class II molecule primarily presents peptides which have been
digested from external sources. Since only antigen presenting cells
(APC) digest foreign protein these are the only cells which normally
express MHC II on their surface.
The path toward the surface of a cell is somewhat different for a
Class II molecule. Within the RER, the alpha and beta proteins of
the molecule associate with each other and a third protein called
the "invariant chain," which stabilizes the complex. In the absence
of the invariant chain, the alpha and beta proteins will not associate.
The MHC-invariant complex is then passed from the RER to, and out
of, the Golgi body. Before it proceeds to the surface of the cell,
the vesicle which contains the complex fuses with an endocytic compartment
where an external protein has been sampled and degraded. In this compartment
the invariant chain is destroyed and part of the degraded protein
will associate with the MHC II molecule in the cleft between the alpha-1
and beta-1 domains. The resulting MHC II-peptide complex will proceed
to the surface where it is expressed. MHC II molecules appear to be
expressed on the surface of cells in pairs. |
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| Exogenous
MHC Class I |
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Though the exact mechanism has yet to be determined, it appears
that in some circumstances, it is possible for certain APCs to ingest
and degrade proteins, and to associate them with MHC I molecules.
This pathway is of particular interest for them developers of vaccines,
who wish to induce a CTL response by inoculation with exogenous
peptides.
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MHC Class I / CTL Interactions |
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Most
cytotoxic T lymphocytes (CTLs) possess both T-cell receptors (TCR)
and CD8 molecules (as well as many other proteins) on their surfaces.
These TCRs are able to recognize peptides, but only when they are
expressed in complexes with MHC I molecules. In order for the TCR
to bind a peptide-MHC complex two requirements must be met. First,
the TCR must have a structure which allows it to bind the peptide-MHC
complex. And second, the accessory molecule CD8, must bind to the
alpha-3 domain of the MHC Class I molecule. Due to genetic recombination
events each CTL expresses a unique TCR which will only bind a specific
MHC-peptide complex. CTLs which recognize/bind to self-peptides (i.e.
peptides which are produced by one's own body as opposed to a foreign
organism or cancerous growth) are eliminated in the thymus or tolerized
by an unknown mechanism following their release from the thymus. As
a result, if a CTL is able to bind to a MHC-peptide complex on the
surface of a cell, this cell is producing a peptide which is not native
to the person.
If this occurs, the CTL will separate from the cell and proceed to
grow and divide. This, and the subsequent development into a mature
killer CTL generally requires additional cytokines from the environment
(most notably, interleukin-2 from TH cells).However, once this maturation
occurs, the CTL and its progeny will proceed to eliminate any cells
which express the same peptide-MHC complex which activated the original
CTL. In addition, some of the progeny of the cell will become dormant
memory CTLs. Though poorly understood, these cells appear to stay
in a resting state until they encounter the peptide-MHC complex they
recognize (e.g. during a reinfection with the same virus) whereupon
they mature into regular CTLs. The MHC I Molecule acts as a means
of assuring that self cells have not been compromised by infection
or mutation. Any cell which is hosting a virus or manufacturing mutant
proteins (as in the case of cancer) will present these foreign peptides
upon its surface. A CTL will recognize them and eventually the cell
will be destroyed. |
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