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 ß2-

microglobulin (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 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

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 open-ended 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