Download MHC Molecules

The Major Histocompatibility
Complex (MHC)
• In all vertebrates there is a genetic region that has a
major influence on graft survival
• This region is referred to as the Major
Histocompatibility Complex (MHC)
• Individuals identical for this region can exchange
grafts more successfully than MHC non-identical
combinations
• Unlike minor histocompatibility antigens, the MHC
products play an important role in antigen recognition
by T cells
Structure of MHC proteins
• The MHC genes and their products are
grouped into 2 classes on the basis of their
chemical structure and biological properties
• The two MHC proteins have a similar
secondary and tertiary structure with subtle
functional differences
Structure of MHC proteins
Structure of MHC proteins
• Class I molecules are made up of one heavy
chain (45 kD) and a light chain called ß2microglobulin (12 KD) that contributes to the
overall structure of the protein
Figure 3-20
Figure 3-20 part 1 of 2
Structure of MHC proteins
• Class II molecules do not contain ß2microglobulin and consist of two (alpha and ß)
chains of similar size (34 and 30 kD)
• Both classes of MHC molecule fold up to
produce very similar 3-D structures
Figure 3-21
Figure 3-21 part 1 of 2
Structure of MHC proteins
• Each has 2 MHC-unique domains which fold together
to form a peptide binding platform
• This structure forms a cleft or groove which
accommodates a peptide
• In both classes the peptide binding "MHC
superdomain" is supported by a pair of
immunoglobulin-like (IgSF) domains
• The differences between the 2 classes are the linear
connectivity of the polypeptide chains and the
dimensions of the peptide-binding groove which
accommodates 8-9 amino acids in class I but is openended for class II
Expression of MHC molecules
• MHC class I molecules are widely
expressed, though the level varies between
different cell types
• MHC class II molecules are constitutively
expressed only by certain cells involved in
immune responses
Figure 3-19
MHC Molecules
MHC Loci
• In man and mouse, as in most species, each class of
MHC is represented by more than one locus
(polygeny), in man these are called HLA for Human
Leucocyte Antigen
• The class I loci are HLA-A,-B and -C
• The class II loci HLA-DR, -DQ and –DP
• All the MHC genes map within a single region of the
chromosome (hence the term Complex)
MHC Molecules
MHC Function
• The products of the MHC play a fundamental role in
regulating immune responses
• T cells must recognise antigen as a complex with
MHC molecules
• This requires antigen to be processed by unfolding
and proteolytic digestion before it complexes with
the MHC molecule
• Once formed the complex of antigenic peptide and
MHC are generally very stable (half life ~ 24hrs)
MHC Molecules
MHC Function
• Thus the biological role of MHC proteins is to
bind small peptides and to "present" these at
the cell surface for the inspection of T cell
antigen receptors
• The allelic variation of MHC molecules is
functionally reflected in the selection of
peptides which can bind
Figure 3-20 part 2 of 2
Figure 3-21 part 2 of 2
MHC Molecules- T Cell Receptors
• T cells requires MHC antigens
MHC Molecules
Peptide Binding to MHC
• Each allelic product has a unique set of peptides which it can bind with
high affinity (though rarely particular peptides may bind to more than
one MHC allele)
• In a normal cell the majority of MHC molecules will be complexed with
self peptides, "empty" MHC molecules are less stable especially in the
case of class I products
• There are 50,000 - 100,000 MHC molecules on a typical cell
• Most 'normal' MHC molecules are occupied by self peptides
• The requirements for binding to a particular allele are met by ~1/1000 1/10000 random peptides
• This would lead to the population of any given MHC allele on a single
cell displaying a very large number of peptides each at only a few
copies per cell
• But there is a restriction on binding to tightly
• This would make it easier for small pathogens to escape the immune
response by having no peptides which bind to a given host's MHC
molecules
MHC Molecules
Peptide Binding to MHC
•
This stringency has to make a balance between allowing too
many peptides to bind
• The typical population of ~100,000 MHC class I molecules of a
single allotype on a normal cell displays >1000 different
peptides
• Individual peptide-MHC complexes are represented in widely
different amounts from 1 - 5000 molecules/cell (mean~100)
• T cells vary in the threshold for activation from a few (1?)
complexes/cell to a few thousand, depending on the affinity,
activation state etc. of the T cell and on the antigen presenting
cell .
Figure 3-22
Figure 3-23
Figure 3-25
Figure 3-27
Figure 3-28
MHC Molecules
Pathways for antigen processing
• The 2 classes of MHC molecule are specialised to present
different sources of antigen
• MHC class I molecules present endogenously synthesised
antigens, e.g. viral proteins
• MHC class II molecules present exogenously derived proteins,
e.g. bacterial products or viral capsid proteins
• The cell biology and expression patterns of each class of MHC are
tailored to meet these distinct roles
• MHC class I molecules are very unstable in the absence of
peptide. They bind peptides in the Endoplasmic reticulum (ER)
• Peptides are generated continuously in the cytoplasm by the
degradation of proteins, predominantly by the proteasome
• Peptides of suitable length (~8-18 amino acids) are specifically
transported across the ER membrane by a heterodimeric
transporter made up of the TAP1 and TAP2 molecules
Figure 1-27
Figure 1-28
Figure 1-28 part 1 of 2
Figure 1-28 part 2 of 2
MHC Molecules
Pathways for antigen processing
• MHC class II molecules bind to a third polypeptide in the ER
called invariant chain or Ii .The invariant chain serves two
purposes. It blocks the binding of peptides to the class II
molecule and it targets the class II molecule to a specialised
endosomal compartment (MIIC). Exogenous antigens enter the
cell in membrane vesicles, either by fluid phase pincytosis or
receptor mediated endocytosis. These vesicles fuse with the MIIC
compartment. The MIIC compartment has an acid pH and contains
proteases, this combination unfolds and degrades both the
antigen and the invariant chain causing the generation of
antigenic peptides and the release of class II molecules to bind
those peptides with appropriate sequence motifs .The class II
molecules, peptide complexed or "empty", then traffic to the
plasma membrane .
Figure 1-29
Figure 1-29 part 1 of 2
Figure 1-29 part 2 of 2