Topic 4: MHC and MHC processing in adaptive immunity

Question 1

What are MHC molecules?

Answer 1

• MHC (major histocompatability complex) molecules are membrane proteins that can bind and display peptides via a peptide binding cleft at the amino-terminal end
• They are encoded by a set of highly polymophic genes
• Can exist in two forms; class I and class II

Question 2

What is the importance of the polymorphic nature of the MHC gene?

Answer 2

• The polymorphic nature of the genes that encode MHC markers in the human population ensures that there will always be some members of the population capable of presenting the proteins of; and therefore mounting an immune response against any particular microbe
• MHC genes are codominant meaning both parental alleles are expressed

Question 3

What is MHC Class I?

Answer 3

• The MHC marker expressed on all nucleated cells (e.g. skin cells, liver cells and APCs)
• Express (usually endogenous) peptides to CD8 T cells
• If a cell becomes infected by a virus or intracellular bacteria or it undergoes cellular transformation the peptide will no longer be a “self” peptide and CD8 cells will target and kill these cells

Question 4

What is the structure of MHC Class I?

Answer 4

• Consists of an alpha chain non-covalently associated with a protein called B2-microglobulin
• The peptide bonding cleft is formed by the polymorphic a1 and a2 domains of the alpha chain and it accommodates peptides 8-11 amino acids is length
• The a3 domain is invarient and specifically only binds a CD8 T cell co-receptor meaning that MHC Class I will only bind to and interact with CD8 T cells

Question 5

What is MHC Class II?

Answer 5

• MHC Class II is expressed on the surface of professional antigen presenting cells such as dendritic cells, macrophages and B cells
• Presents antigen peptide fragments to CD4 T cells

Question 6

What is the structure of MHC Class II?

Answer 6

• Composed of an alpha chain and a beta chain
• The polymophic a1 and B1 domains form the peptide binding cleft that can accomodate peptides 10-30 amino acids in length
• The non-polymorphic a2 and B2 domains bind to CD4 T cell coreceptors

Question 7

What are the 3 different antigen presentation pathways of MHC molecules?

Answer 7

1. Processing of internalised antigens for display by MHC Class II
2. Processing of cytosolic antigens for display by MHC Class I
3. Cross presentation of interalised antigen by MHC Class I

Question 8

Describe the steps in the presentation of interalised antigen by MHC Class II

Answer 8

• MHC Class II generally present peptides from exogenous antigens that have been engulfed by the APC

1. Antigen is phagocytosed by the APC- antigen is inside phagosome
2. Phagosome binds with lysosome and phagolysosome breaks down the antigen protein in the vesicle- creating antigenic peptides within the vesicle
3. MHC Class II molecules are synthesised in the ER
4. The newly synthesised MHC Class II molecules cannot bind peptides as their binding site is attatched to the invariant chain protein which contains CLIP which binds tightly to the a1 and b1 peptide binding cleft (so it cannot bind antigen peptides in the ER)
5. The MHC Class II + Invariant chain protein enter the vesicles containing the antigen peptide
6. Within the vesicle the invariant chain protein degrades and the a protein called DM facilitates the removal of CLIP and the addition of the antigen peptide to the peptide binding cleft of the MHC Class II
7. When a stable peptide-MHC II complex is formed it is transported in a vesicle to the cell membrane where it is incorporated.

Question 9

Describe the steps in the presentation of cytosolic (endogenous) antigen by MHC Class I (normal MHC I presentation)

Answer 9

1. Antigenic proteins are produced inside the cell (e.g. due to a viral infection)
2. These endogenous antigens are targeted for destruction by the ubiquitinion and the proteosome degrades them into peptides
3. The antigen peptides are then present in the cytosol of the cell
4. MHC Class I molecules are produced in the ER
5. The antigen peptides must enter the ER in order to bind to MHC Class I so they are transported by TAP (transporter associated with peptide loading) into the ER
6. Within the ER the peptides are bound to the peptide binding cleft of MHC Class I
7. If a stable peptide-MHC Class I complex is formed it will bud off the ER membrane and be transported via the secretory pathway to the cell surface where it will be incorporated

Question 10

Describe the steps in the presentation of internalised (exogenous) antigen by MHC Class I in dendritic cells (cross presentation):

Answer 10

1. Exogenous antigen is phagocytosed by the dendritic cell
2. Exogenous antigen is within phagosome
3. The exogenous antigen can be degraded and loaded onto MHC Class I via the vacuolar pathway, phagosomal loading or ER loading
4. The exogenous antigen is then presented by the MHC on the dendritic cell

Question 11

Why is cross presentation of exogenous internalised antigens by MHC Class I to CD8 cells required?

Answer 11

• This is neccessary for dendritic cells to activate naive CD8 T cells specific for viral/tumour antigens
• This is required as some viruses will only infect certain cell types (not dendritic cells) and these cells will not travel to the lymph nodes to produce the signals required to initiate T cell activation and activation of cytotoxic T cells
• A subset of dendritic cells has developed the ability ingest infected host cells, dead tumour cells etc and present the antigen peptides in their MHC Class I for recognition by CD8 T cells