The Major Histocompatibility Complex (MHC)

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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

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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

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Structure of MHC proteins
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Structure of MHC proteins

• Class I molecules are made up of one heavy chain
  (45 kD) and a light chain called ß2-microglobulin
  (12 KD) that contributes to the overall
  structure of the protein

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Figure 3-20
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Figure 3-20 part 1 of 2
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Structure of MHC proteins

• Class II molecules do not contain
  ß2-microglobulin 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

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Figure 3-21
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Figure 3-21 part 1 of 2
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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 open-ended for class II

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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

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Figure 3-19
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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)

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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)

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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

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Figure 3-20 part 2 of 2
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Figure 3-21 part 2 of 2
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MHC Molecules- T Cell Receptors

• T cells requires MHC antigens

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MHC MoleculesPeptide 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

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MHC MoleculesPeptide 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 gt1000 different peptides
• Individual peptide-MHC complexes are represented
  in widely different amounts from 1 - 5000
  molecules/cell (mean100)
• 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.

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Figure 3-22
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Figure 3-23
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Figure 3-25
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Figure 3-27
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Figure 3-28
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MHC MoleculesPathways 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

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Figure 1-27
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Figure 1-28
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Figure 1-28 part 1 of 2
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Figure 1-28 part 2 of 2
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MHC MoleculesPathways 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.

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Figure 1-29
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Figure 1-29 part 1 of 2
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Figure 1-29 part 2 of 2