Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

T CELLS AND MHC PROTEINS
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able to bind a very large number of different peptides. The genes encoding class
I and class II MHC proteins (see Figure 24–37) are the most polymorphic known
in higher vertebrates: in the human population, for example, there are more than
2000 allelic variants of these genes. The corresponding variations in the MHC proteins
are concentrated in the floor and walls of the peptide-binding grooves and
allow MHC molecules in different individuals to bind different arrays of peptides.
It is thought that infectious diseases have been an important driving force for
generating this remarkable MHC polymorphism. In the evolutionary war between
pathogens and the adaptive immune system, pathogens will tend to change their
proteins through mutation so that the peptides derived from them will not fit
in the MHC peptide-binding grooves. When a pathogen succeeds, it can sweep
through a population as an epidemic. In such circumstances, the few individuals
who produce a new allelic form of MHC protein that can bind peptides derived
from the altered pathogen will have a large selective advantage. This type of
selection will tend to promote and maintain a large diversity of MHC proteins
in the population. In West Africa, for example, individuals with a specific MHC
allele (HLA‐B53) have a reduced susceptibility to a severe form of malaria that is
endemic there; although this allele is rare elsewhere, it is found in 25% of the West
African population.
The extensive diversity of human MHC proteins is the main reason that individuals
who receive a foreign organ transplant must be treated with strong immunosuppressive
drugs to prevent the immunological rejection of the grafted organ.
Of all the foreign proteins that the graft expresses, the MHC proteins are by far the
most powerful stimulators of the recipient’s T cells, which would rapidly destroy
the graft if they were not prevented from doing so by such drugs. Foreign MHC
proteins are powerful T cell stimulants because T cells respond to them in the
same way they respond to self MHC proteins that have foreign peptides bound
to them; for this reason, the proportion of a person’s T cells that can specifically
recognize any foreign MHC protein is relatively high.
CD8 protein
class I MHC protein
CD4 and CD8 Co-receptors on T Cells Bind to Invariant Parts of
MHC Proteins
The affinity of TCRs for peptide–MHC complexes on an APC is usually too low by
itself to mediate a functional interaction between the two cells. T cells normally
require accessory receptors to help stabilize the interaction by increasing the overall
strength of the cell–cell adhesion. Unlike TCRs or MHC proteins, the accessory
receptors are invariant and do not bind to foreign peptides. Once bound to the
surface of a dendritic cell, for example, a T cell increases the strength of the binding
by activating an integrin adhesion protein (discussed in Chapter 19), which
then binds more strongly to an Ig‐like protein on the surface of the dendritic
cell. This increased adhesion enables the T cell to remain bound long enough to
become activated.
When an accessory receptor has a direct role in activating the T cell by generating
its own intracellular signals, it is called a co-receptor. The most important
and best understood of the co-receptors on T cells are the CD4 and CD8 proteins,
both of which are single-pass transmembrane proteins with extracellular Ig‐like
domains. Like TCRs, they recognize MHC proteins, but, unlike TCRs, they bind
to invariant parts of the MHC protein, far away from the peptide-binding groove.
CD4 is expressed on both helper T cells and regulatory T cells and binds to class II
MHC proteins, whereas CD8 is expressed on cytotoxic T cells and binds to class I
MHC proteins (Figure 24–40).
CD4 and CD8 contribute to T cell recognition by helping the T cell to focus on
particular MHC proteins, and thereby on particular types of target cells. Thus, the
recognition of class I MHC proteins by CD8 allows cytotoxic T cells to focus on
any type of infected host cell, while the recognition of class II MHC proteins by
CD4 allows helper and regulatory T cells to focus on the target immune cells that
they help or suppress, respectively. The cytoplasmic tail of the CD4 and CD8 proteins
is associated with a member of the Src family of cytoplasmic tyrosine kinases
T H
T C
CD4 protein
TCR
class II MHC protein
dendritic cell
or target cell
dendritic cell
or target cell
Figure 24–40 CD4 and CD8 co-receptors
on the surface of T cells. Cytotoxic T cells
(T C ) express CD8, which recognizes class I
MHC proteins, whereas helper T cells
(T H ) and regulatory T cells (not shown)
express MBoC6 CD4, m25.56/24.42
which recognizes class II
MHC proteins. Note that the co-receptors
bind to the same MHC protein that the
TCR has engaged, so that they are brought
together with TCRs during the antigenrecognition
process. Whereas the TCR
binds to the variable (polymorphic) parts
of the MHC protein that form the peptidebinding
groove, the co-receptor binds
to the invariant part, well away from the
binding groove.