Antigen Processing And Presentation
In discussing the MHC and the T-cell receptor (see Figs 11 and 12),
frequent allusion has been made to the
foreign peptides that bind to the former and are recognized by the latter.
These peptides become associated with MHC molecules through two quite separate
pathways (see figure), usually known for convenience as the class I pathway
(left) and the class II pathway (right).
The first evidence that the MHC was
involved in presenting antigens to T cells was the demonstration of ‘MHC
restriction’ – the fact that T cells are specific for both antigen and MHC
molecule. Then it was dis- covered that cytotoxic T cells could respond to
viral nuclear antigens, which are not displayed on the surface of the virus!
How could a T cell ‘see’such a well-concealed antigen? The answer is shown in
the left-hand figure above: virus-derived peptides become bound to class I MHC
molecules inside the cell and are then transported to the surface, where T
cells can recognize the peptide–MHC combination and, under appropriate
circumstances, kill the virus-infected cell (for more details see Fig. 21).
At
the same time,
it was shown
that a rather
similar process occurs in the ‘antigen-presenting’ cells,
mainly macrophages and dendritic cells, which activate helper T cells,
with the
difference that here it is the class II MHC molecules that transport the
peptides to the surface (right-hand figure). This process is kept separate from
the class I pathway by occurring in the endosomal/lysosomal vacuoles in which
foreign material is normally digested (see Fig. 9). B lymphocytes can also
process and present antigen, but only when they are able to bind it via their
surface immunoglobulin (top right). Presentation by B cells to T cells is an
essential step in T-cell help (see Fig. 19).
One can now appreciate that the
real role of the MHC system is to transport samples of intracellular
proteins to the cell surface for T cells to inspect them and react if
necessary – by proliferating into clones and then helping macrophages or B
cells or killing virus-infected cells, as described in the following pages.
Virus Because they are synthesized in the cell, viral
proteins are avail- able in the cytoplasm, alongside self-proteins.
RER Rough endoplasmic reticulum, where proteins,
including those of the MHC, are synthesized.
MHC I The single three-domain α chain associates with
β2- microglobulin to make a class I MHC molecule, whose structure is not
fully stable until a peptide has been bound (see below). The effi- cient
folding of MHC molecules around an antigen peptide requires a set of other
‘chaperone’ molecules found within the RER.
Proteasome A cylindrical complex of proteolytic enzymes
with the property of digesting proteins into short peptides. This organelle has
an essential role in regulating protein turnover in all cells. Its function has
been hijacked by the immune system to provide peptides for class I MHC
presentation. Two components of the proteasome that can alter its properties so
as to produce peptides with better binding properties for MHC are encoded by
the LMP genes that are found within the MHC region of the chromosome.
TAP TAP (transporter of antigen peptide) genes are
found within the MHC region of the chromosome, and encode transporter proteins
that carry the proteolytic fragments of antigen generated by the proteasome
from the cytosol into the lumen of the endoplasmic reticulum where they bind to
the peptide-binding groove of the class I MHC. Some viruses (e.g. human
papillomavirus [HPV], Epstein – Barr virus [EBV], cytomegalovirus [CMV]; see
Fig. 27) diminish immune recognition by encoding proteins that block TAP
function or peptide binding to MHC.
Peptides of 8–10 amino acids are able to bind into the
groove between the outer two α helices of the MHC molecule. If the peptides
produced by the proteasome are too long special ‘trimming’ enzymes in the RER
cut them to the right length. This binding is of high affinity but not as
specific as that of antibody or the TCR. Thus, the six different types of class
I MHC molecules on each cell (see Fig. 11) can between them bind a wide range
of peptides, including many derived from ‘self’ proteins. Even after viral
infection only a few percent of the available MHC molecules become loaded with
viral peptides, and the rest will be derived from ‘self’ proteins from within
the cell.
Golgi The Golgi complex, responsible for conveying
proteins from the RER to other sites, including the cell surface.
TCR The T-cell receptor. Because of selection in
the thymus (see Fig. 16), only a T cell whose receptor recognizes both the MHC
molecule and the peptide bound in it will respond. This is a highly specific
interaction, ensuring that cells displaying only ‘self’ peptides are not
killed.
CD8 This molecule, expressed on cytotoxic T cells,
recognizes the class I MHC molecule, a further requirement before killing of
the virus-infected cell by the cytotoxic T cell can take place.
Cross-presentation Some antigens ‘break the rules’ and enter the
class I processing pathway from the outside of the cell. Dendritic cells appear
to be particularly efficient at cross-presentation, which may be of importance
in trying to stimulate an immunological response against tumours (see Fig. 42).
against tumours (see Fig. 42).
The class II pathway
Antigen Any foreign material taken in by phagocytosis
or endocytosis will find itself in vesicles of the endocytic pathway, collectively
known as endosomes, but including the acidic lysosomes, so that various
digestive enzymes can act at the appropriate pH. In the case of microbial
infection, the whole microbe is taken into the phagolysosome. Macrophages and
dendritic cells carry many receptors on their surface (see Figs 3 and 5), which
can bind sugars or other common constituents of pathogen surfaces and greatly
increase the efficiency of uptake, by receptor-mediated uptake.
Sig Surface immunoglobulin allows the B lymphocyte
to bind and subsequently endocytose antigen. Once within the cell, the antigen
is processed in the usual way and peptides are presented on class II MHC.
Because uptake is via a specific receptor, B cells selectively process only
those antigens against which they carry specific antibody.
MHC II The two-chain MHC class II molecule forms a
peptide- binding groove between the α1 and β1 domains, the β chain contributing
most of the specificity. When first synthesized, this binding is prevented by a
protein called the invariant chain, which is progressively cleaved off
and replaced by newly produced peptides in the endosomes.
Inv (invariant chain) So called because, in contrast to the class II
MHC molecules, it is not polymorphic. It acts as a ‘chaperone’ in helping MHC
molecules to fold correctly as they are synthesized, and then binds to them,
preventing peptides from associating with the peptide-binding site while still
within the endoplasmic reticulum. It then directs the transport of the
associated class II MHC molecules to specialized processing endosomes where,
finally, it is proteolytically cleaved. This allows antigen peptides to bind
the MHC, and allows the MHC carrying the peptides to exit the endosome and go
to the cell membrane.
Peptides MHC class II molecules can bind peptides up to
20 amino acids long, which can extend out of each end. The peptides include
some derived from microbes in the endosomes (e.g. persistent bacteria such as
the tubercle bacillus), but also includes many self-peptides, some of which are
derived from MHC molecules themselves. Peptides carrying post-translational
modifications such as sugars or phosphate groups are also presented.
LC (class II loading compartment) Specialized
acidic endosomes within which peptides are loaded on to the
peptide-binding cleft of MHC class II molecules. The binding of peptides to MHC
within this compartment is facilitated by two other class II-like molecules,
HLA-DM and HLA-DO, which ensure that only those peptides with the best MHC fit
are presented at the cell surface.
CD4 This molecule, expressed on helper T cells,
interacts with MHC class II molecules, ensuring that the T-cell response (i.e.
cytokine secretion; see Figs 21 and 23) is focused on an appropriate cell, i.e.
either a B lymphocyte or a macrophage harbouring an intracellular infection.
Thus, the type of T-cell response that occurs is determined by a sequence of
factors: (i) the type of T cell (CD8 cytotoxic or CD4 helper); (ii) the class
of MHC (I or II); (iii) the source of the peptide bound by the MHC (cytoplasmic
or endocytosed); and, ultimately, (iv) the type of infection (viral or
microbial). However, there are exceptions to this tidy scheme as described in
Figs 26–32.
