MHC Class I and II Antigen Processing

Question 1

What are the types of APCs?

Answer 1

Dendritic cells
Macrophages
B cells

Question 2

Where are DCs found?

Answer 2

Under most surface epithelia and in solid organs

Question 3

What does DC migration induce?

Answer 3

Maturation

Question 4

What attracts DCs to the lymph nodes?

Answer 4

Specialised blood vessels - high endothelial venules (HEV) secrete a chemokine CCL21 that attracts DCs
CCL21 also contributes to DC maturation

Question 5

What is meant by histocompatibility?

Answer 5

Tissue compatibility

Question 6

Where are MHC structures found?

Answer 6

MHC class I and II proteins found at cell surface and form a structure that holds antigenic peptides for surveillance by T cells

Question 7

What recognises MHC I?

Answer 7

CD8+ cytotoxic T cells

Question 8

What recognises MHC II?

Answer 8

CD4+ helper T cells

Question 9

What is the major histocompatibility complex?

Answer 9

Large gene complex on chromosome 6 which encodes multiple proteins involved in immune response

Question 10

What is the structure of MHC I?

Answer 10

Alpha 1, 2, 3
Beta 2 microglobulin

Question 11

What is the structure of MHC II?

Answer 11

Beta 1, 2
Alpha 1,2

Question 12

Describe MHC I

Answer 12

Humans = HLA-A, B, C
Found in all nucleated cells
2 polypeptides non-covalently bound

Question 13

Describe the alpha chain of MHC I

Answer 13

45kDa
Inserted in membrane
Glycosylated
Polymorphic

Question 14

Describe beta 2 microglobulin in MHC I

Answer 14

12kDa
Not inserted in membrane
Not glycosylated
Not polymorphic

Question 15

Describe MHC II

Answer 15

Humans = HLA-DR, DP, DQ
Found on professional APCs
2 polypeptides non-covalently bound

Question 16

Describe the alpha and beta chains of MHC II

Answer 16

Both 30kDa
Both inserted in membrane
Both glycosylated
Both polymorphic

Question 17

What are the differences between the peptide binding groove of MHC I and II?

Answer 17

Class I bind short peptides 8-10 amino acids long
No length constraints on peptides bound by class II but usually 13-17 amino acids long

Question 18

What feature of peptide presentation do MHC molecules have?

Answer 18

Most MHC molecules can present multiple peptides (but most peptides will not bind to a given MHC molecule)

Question 19

How are so many different peptides recognised by so few invariant MHC molecules?

Answer 19

2 alleles of each of MHC I genes (HLA-A, B, C)
3 alleles of each of MHC II genes
So the actual specificity for an antigen is lower than seen with B cell or T cell

Question 20

Where are polymorphisms found?

Answer 20

In the upper peptide-binding part of the MHC protein

Question 21

What is the proteasome?

Answer 21

Cytoplasmic structure that digests proteins
- Mechanism for removing poorly folded or damaged proteins
- These proteins have been tagged for destruction by addition of ubiquitin
- So produced peptides from all internal proteins

Question 22

Where does the proteasome digest proteins?

Answer 22

In the cytosol

Question 23

What can the proteasome not do?

Answer 23

Cannot distinguish between self and non-self proteins

Question 24

What happens to the short peptide fragments?

Answer 24

They are transported to the ER lumen via TAP transporters

Question 25

What are TAP transporters?

Answer 25

Transporter associated with antigen processing Endoplasmic reticulum membrane proteins

Question 26

What do TAP transporters do?

Answer 26

Transport peptides from cytoplasm into ER lumen Associate with newly synthesised class I molecules and helps to load peptides into their groove

Question 27

When must stable complexes be formed?

Answer 27

Before the MHC can exit the ER

Question 28

What do chaperones do?

Answer 28

Stabilise the complex and assist with refolding in the ER

Question 29

What is the first of the chaperones?

Answer 29

Calnexin

Question 30

What is the role of calnexin?

Answer 30

Keeps the binding site of MHC I open so the peptide can be loaded

Question 31

What happens while calnexin keeps the binding site open?

Answer 31

Endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP) further trims the peptide The trimmed peptide can then bind to the cleft in MHC I so calnexin no longer needed and beta-2-microglobulin can bind

Question 32

What is MHC II restricted to?

Answer 32

Professional APCs - DCs, macrophages, B cells

Question 33

What recognises MHC II?

Answer 33

CD4+ T cells

Question 34

How does antigen presentation occur?

Answer 34

Antigen taken up from extracellular space into intracellular vesicles In early endosomes of neutral pH, endosomal proteases are inactive Upon acidification of vesicles, proteases are activated These degrade the antigen into peptide fragments The vesicles then fuse with endosomes and processed peptides are loaded into MHC II

Question 35

When do MHC II encounter their peptide antigens?

Answer 35

After they have left the ER (they must not bind the intracellular peptide fragments they encounter in the ER) However stable complexes must be formed before MHC can exit the ER

Question 36

What is the solution for forming MHC II stable complexes?

Answer 36

Invariant chain (Ii) binds in the groove of MHC II and acts as a chaperone This directs the MHC II complexes towards endosomal compartment of the cell

Question 37

What happens to the invariant chain once MHC II complexes exit the ER?

Answer 37

It is degraded to leave a short peptide called CLIP (class II-associated invariant-chain peptide)

Question 38

What is required to remove CLIP to allow antigenic peptides to bind?

Answer 38

A specialised protein, HLA-DM, binds to CLIP and releases it to allow other peptides to bind MHC II then travels to the cell surface

Question 39

What cells express MHC I?

Answer 39

All nucleated cells Meaning all virus infected or transformed cells should present foreign or new antigens on MHC I Cytotoxic T cells will be able to respond to these, however there is the problem of cross-presentation

Question 40

How does cross-presentation arise?

Answer 40

Naive cytotoxic T cells must be primed by profession APCs, usually DCs But DCs are known to ingest external Ags, process them and present them via MHC II This will not allow the priming of CD8+ T cells DCs usually have a range of specialised processes to allow processing and prestation of external Ags through MHC I, which is known as cross-presentation

Question 41

What are the 2 pathways in which cross-presented antigens can encounter MHC?

Answer 41

Cytosolic pathway Vacuolar pathway

Question 42

What might determine the cross-presentation pathway?

Answer 42

Size of ingested particles - smaller particles = phagosome-cytosol pathway - larger particles = vacuolar Large particles may also require recruitment of extra membrane from ER, bringing ER proteins with it

Question 43

What role does autophagy have in antigen presentation?

Answer 43

Allows controlled degradation and recycling of cellular components

Question 44

Where does degradation occur?

Answer 44

Lysosomes