Adaptive immunity 3

Question 1

What are the three main types of professional antigen-presenting cells?

Answer 1

Dendritic cells-> broadest range of antigen presentation. activated DCs -> potent THcell activators as they expressco-stimulatorymoleculesCD80 + CD86.
Macrophages -> engulfs pathogens + processes into immunogenic peptides.
B-cells -> internalises antigen -> binds to BCR + present it incorporated to MHC II molecule.

Question 2

How are T cells activated?

Answer 2

APCs determine which peptides will be presented on class I + II MHC during initial activation. 
T cells need to distinguish between external antigens taken up by APCs + internal antigens -> infected cell.

Question 3

What are the locations of MHC class I and MHC class II molecules?

Answer 3

MHC class I-> allnucleatedcells (not just APCs) + typically presentintracellular antigens-> viruses.
MHC class II-> only onAPCs+ typically  presentextracellular antigens -> bacteria.

Question 4

What is antigen processing and what does it require?

Answer 4

Enzymatic process of degrading proteins through proteases into antigenic peptides.
ATP + movement of endocytic vesicles.

Question 5

How are antigens processed in class I MHC molecules?

Answer 5

Intracellularpeptides made by proteases -> proteasome in cytosol transported into ER for further processing.
Antigens presented recognised by CD8+ cytotoxic T cells to kill infected or tumour cells.

Question 6

How are antigens processed in class II MHC molecules?

Answer 6

Processingexogenousantigensbegins with endocytosis of antigen -> encased within endosomes that acidify + activate proteases to degrade antigen.
MHC class II transported into endocytic vesicles -> bind to peptide antigen + travel to cell surface.
Antigens presented are recognised by CD4+ helper T cells.

Question 7

What are the endogenous antigens proteasomes and what are their actions?

Answer 7

Standard proteasome, immuno-proteasome, thymo-proteasome.

Unfolds proteins + cleaves into peptides + amino acids.

Question 8

What is the purpose of TAP (Transporters associated with Antigen Processing) proteins?

Answer 8

Endogenous antigens:
TAP 1 + TAP 2 form heterodimer in membrane of ER to facilitate selective transport of peptides from cytoplasm into lumen of ER.

Question 9

What is the structure of MHC class I molecules and how does TAP interact with peptides?

Answer 9

MHC class I assembled inER -> polymorphicheavy chain (alpha)+ β2-microglobulin chain.
Heavy chain stabilised by chaperonecalnexin -> associated with β2-microglobulin.
Without peptides, they’re stabilised bychaperone proteins: calreticulin, Erp57, PDI + tapasin. complex of TAP, tapasin, MHC class I, ERp57 + calreticulin ->peptide-loading complex(PLC).
Peptides derived from degradation of proteins mediated by cytosolic + nuclear proteasomes.
Tapasin interacts with TAP protein which translocates peptides from cytoplasm into ER.
TAP translocates peptides of 8–16 aa + may require additional trimming in ER before binding to MHC class I perhaps due to presence of ER aminopeptidase (ERAAP) associated with antigen processing.

Question 10

Which cells are required for the eradication of infected cells?

Answer 10

Effector CD8+ Tc (CTLs) activated by endogenous or intracellular antigens.
CTLs also activated against cancer cells (tumour) targets “neo antigens”.
Antigens stimulating CTLs must be produced inside cell to alert immune system of an intracellular infection.

Question 11

How can some pathogens evade the immune system?

Answer 11

Viruses can interfere with Class I MHC expression to escape killing by CTLs.
Herpes simplex virus protein ICP47 can selectively bind to TAP + inhibit transfer of peptides into ER. inhibits production of invariant chain peptide.
Some parasites invade de-nucleated red blood cells, which don’t express MHC I.
HIV interferes with Class II processing
Leishmania + mycobacteria (TB) prevent phagosome-lysosome fusion.

Question 12

How are peptides generated?

Answer 12

Peptides bound to MHC Class II derived from engulfed pathogens.
Acidification -> lysosome fuses with endosome + activates proteases that degrade proteins into fragments.
protein is digested into peptides in phagolysosome. 
vesicles containing peptides fuse with vesicles containing MHC class II -> allows peptide fragments to be loaded on to MHC class II.

Question 13

Outline the trafficking of MHC class II molecules

Answer 13

MHC class II alpha + beta chains associate in ER.
In trans golgi network MHC class II is sorted into vesicles
which deliver MHC class II to specialised compartments where peptide loading occurs.

Question 14

What prevents MHC class II from binding “self” peptides in the ER?

Answer 14

Complex of MHC II + invariant chain is transported through Golgi into MHC class II compartment. 
Acidic pH -> cathepsin proteases activated + digest invariant chain -> CLIP -> exchanged for antigen peptide derived from protein degraded in endosomal pathway. requires chaperone HLA-DM or HLA-DO for MHC class II + catalyses release of CLIP when antigenic peptide is present. MHC II loaded with foreign peptide + transported to cell membrane to present cargo to CD4+ T cells.

Question 15

What is exogenous pathway MHC II peptide loading essential for?

Answer 15

CD4 Th cells to recognise exogenous peptide.
Critical element -> invariant chain is degraded + CLIP is exchanged with foreign peptide.
Macrophage is activated + production of secreted antibody by plasma cells.

Question 16

How are T-cell antigens kept apart?

Answer 16

Class I + Class II MHC both traverse through ER to cell surface but load peptides in different cell compartments.
Control is through accessory proteins:
Class I requires TAP, Tapasin
Class II requires low pH for removal of invariant chain + produce CLIP.