Lecture 9: Mechanisms of Antigen Presentation on MHC

Question 1

Why do we have antigen presentation?

Answer 1

there are lots of intracellular parasites such as protozoans, bacteria and viruses which prefer living inside cells

Question 2

How can T cells “peek” inside infected cells?

Answer 2

they don’t have to and instead examine the trash i.e. antigen presentation consists of displaying material that is part of the normal metabolism of cells which can provide information to the immune system about what is going on inside the cell

Question 3

What happens when an infectious agent like a virus is present inside a cell?

Answer 3

causes a change in the material displayed by a cell e.g. abnormal proteins which can be detected by the immune system

Question 4

What happens when a cell mutates into a form which could cause cancer?

Answer 4

those mutations can be displayed on the surface which can provide the basis for the ability of the immune system to fight cancer cells and destroy them

Question 5

What is the role of MHC?

Answer 5

bind and display peptide antigens on the surface of the cell

enables antigen presentation

Question 6

What are included in the antigenic determinants recognised by T cells?

Answer 6

residues from both the antigenic peptide and the MHC molecule
this is the structural basis for MHC restriction

Question 7

What are the steps involved in the process of MHC class I antigen presentation?

Answer 7

infection e.g. virus -> synthesis of viral antigens -> proteasome degrades the antigen generating antigenic peptides -> peptides enter ER, where MHC I is synthesised -> peptides are inserted into the binding site of MHC I -> MHC I + peptide complex is transported along the secretory pathway to the plasma membrane

Question 8

How are peptides able to enter the ER?

Answer 8

TAP translocates the peptides into the ER

Question 9

What happens in the absence of pathogens?

Answer 9

MHC I molecules present self components

MHC I antigen presentation occurs constitutively (ongoing)

Question 10

What does antigen presentation inform about?

Answer 10

the “health” of the cells; alterations in the proteome will be “sensed” as changes in the peptide repertoire displayed on the surface

Question 11

What is the goal of MHC I presentation?

Answer 11

to display in real-time on the plasma membrane a sample of all the proteins synthesised by the cell

Question 12

What is the MHC I presentation machinery is a combination of?

Answer 12

“multifunctional” proteins co-opted for an antigen presentation role, and “dedicated” proteins whose primary function is to assist in antigen presentation

Question 13

What are “altered self” proteins also presented together with? Which obstacles must be overcome to deal with this?

Answer 13

presented together with “normal self” proteins

this requires to overcome obstacles imposed by the inherent physico- chemical properties of cellular structures

Question 14

Where in the cell can pathogens live?

Answer 14

within endosomal compartments e.g. bacteria TB

Question 15

Why can pathogens live within endosomal compartments? What is required in these situations?

Answer 15

because these compartments are separated from the proteasome
MHC class II is required in these situations

Question 16

What is the role of “professional” antigen presenting cells?

Answer 16

actively capture pathogens and present pathogen fragments to T lymphocytes

Question 17

What are the steps involved in the process of MHC class II antigen presentation?

Answer 17

the APC endocytoses antigen -> endosomal proteases degrade the antigen -> the antigenic peptides are contained in endosomal compartments -> MHC II is synthesised in the ER -> MHC II binds the antigenic peptides -> MHC II peptide complexes are transported to the plasma membrane

Question 18

What happens if you acidify a location where a protein is e.g. endosomal compartments?

Answer 18

the protein denatures which makes it much more accessible to proteolysis

Question 19

How does acidification occur in endosomal compartments?

Answer 19

H+-pump ATPases lower the pH of endosomal compartments

Question 20

How does reduction of S-S bonds occur in endosomal compartments?

Answer 20

GILT (g-interferon Inducible Lysosomal Thiol reductase) cleaves disulfide bonds

Question 21

What are endosomal compartments?

Answer 21

highly proteolytic regions of the cell which are in charge of the turn-over of endogenous membrane proteins and endocytosed extracellular proteins

Question 22

How do MHC I and MHC II differ?

Answer 22

MHC I peptide-binding site is formed by the heavy chain alone while MHC II peptide-binding site is formed by ɑ and β chains combined

Question 23

What is the implication of MHC II being synthesised in the ER?

Answer 23

they have to traffic to the endosomal compartments where antigenic peptides are generated

Question 24

What must MHC II molecules associate with due to the ER containing unfolded polypeptides and peptide ligands for MHC I? What does this prevent?

Answer 24

the invariant chain (li) to prevent binding of ER components

Question 25

Which components associate with MHC II in the ER?

Answer 25

three MHC II ɑβ dimers which form an [ɑβli]3 nonamer

Question 26

What is the role of a “zipper” region in the li?

Answer 26

promotes formation of a trimer

Question 27

What is the role of the CLIP region of li?

Answer 27

occupies the peptide binding site of the ɑβ dimer

Question 28

What is the CLIP region of li?

Answer 28

CLIP is a promiscuous peptide and fits in the peptide binding site of all MHC II allotypes

Question 29

Why does li carry a “molecular code” in its cytoplasmic portion?

Answer 29

because this code “tags” MHC II-Ii for transport to the endocytic route; the complexes would otherwise traffic directly to the PM (like MHC I molecules)

Question 30

What does the substitution of antigenic peptides for CLIP require?

Answer 30

li degradation and the chaperone HLA-2DM/H2-DM

Question 31

What are the steps involved in the process of antigenic peptide substitution for CLIP?

Answer 31

a yet unknown protease cleaves the “zipper” region of Ii to generate Ii-p10, releasing three ab dimers -> cathepsin S cleaves Ii-p10 at the edge of the peptide binding site, generating ab-CLIP -> the chaperone HLA-DM interacts with ab-CLIP, inducing an “open” conformation in the ab dimer -> CLIP is substituted by an antigenic peptide

Question 32

MHC I presents antigens degraded in…

Answer 32

the cytosol (mostly “endogenous”)

Question 33

MHC II molecules present antigens degraded in…

Answer 33

the endosomes (both “endogenous” and “exogenous”)

Question 34

What is MHC I expressed by?

Answer 34

(almost) all cells, because any cell can become infected with a virus, or become a tumour cell

Question 35

What is MHC II expressed by?

Answer 35

specialised APCs which can capture antigens and “communicate” with T cells

Question 36

What is the difference between MHC I and MHC II presentation?

Answer 36

in MHC I presentation the APC is normally infected with a virus, or is a tumour cell while in MHC II presentation the APC may not be infected itself, it just captured the antigen from the surrounding medium and is displaying it to T cells

Question 37

What do cytotoxic CD8+ T lymphocytes interact with?

Answer 37

MHC I

Question 38

What do helper CD4+ T lymphocytes interact with?

Answer 38

MHC II

Question 39

How do T cells recognise antigens presented by MHC I and MHC II?

Answer 39

using different co-receptors