Antigen processing Flashcards
What does antigen presentation mean?
What proteins are involved?
What is important for effective immune responses?
- One cell type ‘presents’ antigen fragments to another cell type
- Cell surface proteins involved – MHC (major histocompatibility complex; also known as human leukocyte antigen/HLA in humans)
- Proteins made by the cell that pick up antigen on their way to the cell surface
- BUT the way these proteins pick up antigen and WHO they present it to is very important for effective immune responses
Why do we need antigen presentation?
Is the site of infection the site of organisation?
- It’s an extra level of control (APC’s send signals that tell T cells when to proliferate)
- We don’t want the immune system to react to everything that is foreign (food, dust in the air, fetus)
- In order to react, the immune system needs to be told that something specific is causing damage e.g. bacteria produce toxins recognised by dendritic cells
Site of infection (where inflammatory response is happening) is not the side of organisation e.g an infection is in your throat but you would have swolen lymph nodes because the immune response is coordinated here
What does MHC class I presents antigen to?
CD8+ cytotoxic T cells: TC
Specificially kill virus infected cells so only respond to antigens presented on MHC class I which takes antigens that are inside the cells and present them on their surface to be recognised by CD8+ T cells
What does MHC class II presents antigen to?
State another function of these cells?
CD4+ helper T cells: TH
Only APC’s express MHC class II which is loaded with pathogens from outside the cell and they are processed inside and then loaded on MHC class II where it can be recognised by CD4+ T helper cells
Coordinate antibacterial responses and helps B cells make antibodies
Which cell express MHC class I?
Which cells express MHC class II?
- All (nucleated) cells express MHC class I (this allows it to be infected by a virus)→Everyone can talk to TC
- Only specialised cells express MHC class II (APC’s)→Limited conversations with TH
Describe the structure of MHC class I
Desccribe the structure of MHC class II
Draw a diagram to show the interaction between MHC class I and a cytotoxic T cell and an MHC class II and a helper T cell
MHC class I:
- 1 chain with 3 subunits
- Alpha 1, 2 and 3 subunits + Beta-2 microglobulin
- One transmembrane domain
MHC class II:
- 2 chains, each with 2 subuints
- (Alpha 1 and 2 + Beta 1 and 2)
- Two transmembrane domains
MHC Class I: the genes
In humans, there are three MHC Class I genes, what are they?
- HLA-A
- HLA-B
- HLA-C
6 MHC class I alleles
What happens when you have an infected cell caused by:
(a) an intracellular microbe
or
(b) an extracellular microbe?
- Intracellular microbe e.g. virus
Those antigens associate with MHC class I and then associate with cytotoxic T cells
- Extracellular microbe
Brought inside the cell, processed and the antigen is presented on MHC class II for helper T cells
MHC Class II: The genes
There are five MHC Class II genes, what are they?
- HLA-DP
- HLA-DM
- HLA-DO
- HLA-DQ
- HLA-DR
10 MHC class II alleles
Describe MHC expression
How many MHC class I molecules can each human make?
How many MHC class II molecules can each human make?
MHC expression is co-dominant and we have two sets of chromosomes; therefore, each human can make up to six MHC Class I molecules and ten MHC Class II molecules (haplotype)
Is MHC polygenic?
Is MHC polymorphic?
Yes MHC is POLYGENIC
- In the human population, there are lots of slightly different genes for each HLA
- e.g. 125 variants of HLA-A
- The proteins encoded are all kind of similar, only a few amino acids different
Yes MHC is POLYMORPHIC
- Many different variations
- They have many different alleles
MHC Class I: the protein
How do the forms of MHC class I differ?
Give an analogy
They bind to peptides that are how many amino acids long?
- The different forms of MHC have slightly different binding grooves
- So they each present slightly different peptides
- As each person expresses six different MHC Class I alleles, each person has the ability to present a wide variety of peptides
- The peptide in the groove is like a falafel in a pitta bread
- MHC I are only choosy about the two anchor residues at the ends of peptides, they don’t mind what’s in the middle
- MHC I binds small peptides 8-11 amino acids long,
Take home message: Any given MHC Class I molecule can present a large number of different peptides that fit within the binding groove
In the image:
White = MHC binding groove
Red = peptide
Explain Antigen presentation in MHC Class I
What is the difference between what T cells detect and what natural killer cells detect?
- MHC I display endogenous peptides from INSIDE the cell, usually derived from a virus but it also contains your own peptides
- Ordinary cellular proteins (enzymes etc.)
- Proteins encoded by viruses and parasites that have entered the cell
- MHC I display a sample of all the proteins being made in that cell
- TC inspect the peptide fragments in the MHC I
- Cells are open books, constantly being read to see whether any pathogenic invasion has occurred
- If a Tc detects non-self or altered self peptides – the infected/damaged cell is destroyed
- If an NK cell detects no MHC Class I (virus trying to hide), the cell is destroyed
Explain the need for Endogenous antigen processing:
What happens to old or worn out proteins?
Where does this occur?
What does this strategy allow us to detect?
- Mistakes during processing or old and worn out proteins need to be disposed of
- ‘Wood-chippers’(the proteasome) in the cytoplasm will chop these proteins up into peptides
- This happens for all the proteins your cells are making – even if these proteins are not yours (pathogen)
- This strategy allows us to detect intracellular viral infection
- Very important as antibodies can’t get inside cells to defend
Explain endogenous antigen processing
TAP transports peptides into the ER
- Your protein or a viral protein is chopped up in the proteosome to create small peptides
- Transporter protein TAP, transports peptides into the endoplasmic reticulum
- MHC class I needs to be transcribed and translated (comes in to the ER from the ribosomes) at the same time peptides are loaded on as its moving into the Golgi apparatus from the ER and is transported to the cell surface
MHC Class II: protein
What is the binding groove like?
Give an analogy
- MHC Class II binding groove is open at the ends
- Longer peptides can fit in – 13-25 amino acids
- The peptide in the groove is like a hotdog in a bun
- Peptides have many anchor residues along their length
Take home message: Any given MHC Class II molecule can present a large number of different peptides that fit within the binding groove
For the image:
White & blue = MHC binding groove
Red = peptide
Choosing the right peptide:
What guides MHC II into endosomes?
What are the functions of enzymes in the endosome?
What is CLIP?
What is CLIP removal facililtated by?
- The invariant chain protein guides MHC II into endosomes
- MHC II waits to pick up its peptide in the endosomes
- Extracellular proteins are taken into the cell in a phagosome (just like phagocytosis)
- Phagosome fuses with the endosome (conetents mix)
- Enzymes in the endosome chop the protein into bits
- Enzymes in the endosome chop the invariant chain peptide up to leave a fragment called CLIP (class II associated invariant chain peptide) in MHC II
- CLIP removal is facilitated by acidic conditions and catalyzed by HLA-DM (not an MHC class II molecule)
- Finally, CLIP is released, this frees up the binding groove to bind an exogenous peptide for display
- Antigens that are in the endosome fused with the phagosome can be loaded onto MHC class II
What is the take home message for antigen processing?
- Two antigen processing pathways with separate peptide loading sites
- MHC Class I - what’s going on INSIDE the cell; displays endogenous peptides to killer T cells
- MHC Class II - what’s going on OUTSIDE the cell; e.g. bacteria, allergens, parasitic worm and displays exogenous peptides to helper T cells
What are the two pathways of antigen processing?
Endogenous (antiviral response- virus is taken up at site of infection and gets processed through the endosomal pathway and peptides get loaded onto MHC class I in the ER
Exogeous pathway (extracellular bacteria, dendritic cells engulf bacteria and process them through an endosome at the same time MHC class II is produces another intracellular vesicle, the vesicles merge and you get loaded MHC class II on the surface
