4 - Adaptive immunity: Antigen Processing and Presentation

Question 1

What are the first cytokines after the pathogen encounter? What do these have in common?

Answer 1

IL-1, IL-6, TNF-alpha

All three are acute phase proteins made by the liver and increase when there’s inflammation.

Question 2

What three molecules are responsible for increasing neutrophils after IL-1, IL-6, and TNF-alpha have been released? What is the function of each?

Answer 2

1. G-CSF:Granulocyte colony stimulating factor
2. GM-CSF: granulocyte-monocyte colony stimulating factor

^Go to bone marrow to increase release.

3.IL-8: chemotactant that calls in neutrophils (clean up on IsLe 8).

Question 3

What two signals are needed for CO-activation of T-cells?

Answer 3

TCR (T cell receptor) interacting with the antigen being displayed by the MHC complex on the antigen presenting cell.

AND

CD28 on the surface of the Tcell interacting with B7-1/B7-2 on the antigen presenting cell.

Question 4

What type of interaction results in NO Tcell response?

Answer 4

TCR reacting with the antigen being shown by the MHC on the antigen presenting cell (APC)

CTLA4 receptor on the Tcell interacting with the B7-1/B7-2 on the APC.

Question 5

What three things occur when a T-cell is activated?

Answer 5

1. Upregulate CD40L expression on its surface for B-cell stimulation
2. Express IL-2 and IL-2 receptor; IL-2 will induce T-cell proliferation
3. Increase DNA synthesis to allow T-cell proliferation

Question 6

What is the function of TH1 cells (Tcells)?

Answer 6

Activate macrophages to kill intracellular or extracellular bacterial pathogens

Question 7

What is the function of TH2 cells (Tcells)?

Answer 7

Mostly used to eliminate eukaryotic pathogens (helminth).

Question 8

What is the function of TREG cells (Tcells)?

Answer 8

Anti-inflammatory; have ability to slow down/inhibit overactive immune reactions.

Question 9

What is the function of TH17 cells (Tcells)?

Answer 9

Involved with reactions to extracellular bacteria, fungi, and autoimmune reactions.

Question 10

How are B cells activated?

Answer 10

They need to be activated by T helper cells.

Bcells produce immunoglobulins. (T cells tell B cells what type of immunoglobulins will be helpful)

Question 11

What allows TH1 cells to activate macrophages?

Answer 11

IFN-Y

Question 12

What is CDT8 Tcell mediated cytotoxicity associated with? How does this work?

Answer 12

The response to viral pathogens.

When a virus infects, the cell will increase release of INFalpha and IFNbeta, interferons that activate NK cells and increase BD8 T cell mediated cytotoxicity.

Question 13

What type of immune cells are responsible for eliminating the source of a virus within the cell?

Answer 13

T cells

Question 14

How do bacteria get into cells?

Answer 14

macrophages, dendritic cells, and B cells engulf them and they are ingested into the endocytic pathway.

Question 15

An effective immune system has to devise a system to samples what two things? What receptors are associated with each location?

Answer 15

Vacuolar - MHC class II receptors

Cytoplasmic compartments - MHC class I

Question 16

Do pathogens bind directly to Tcell MHCs? What has to occur?

Answer 16

All proteins, including those of foreign pathogens, are degraded into peptides.

These peptide fragments are presented to T cells on class 1 or class II MHC molecules.

If the peptide is foreign, the t cell can kill it.

Question 17

How do class I and class II MHC antigen presentation differ?

Answer 17

The source of the peptides that load onto the MHC molecules.

Class 1: inside of the cell (cytoplasm)

Class II: outside the cell (including vacules)

Question 18

What must occur for class 1 MHC antigen presentation to T cells?

Answer 18

1. Proteins ubiquitinated
2. Proteolysis to generate peptides
3. Peptides delivered to class I MHC molecules
4. Peptides bind to class I MHC molecules
5. Peptides must be displayed to T cells in the context of class 1 MHC molecules.

Question 19

How are proteins tagged for proteolysis?

Answer 19

Ubiquitin, a small 8 kDa protein) is added to lysine residues to form a poly Ub chain.

Question 20

What three types of protease activity is associated with the proteasome?

Answer 20

Chymotrypsin-like
Trypsin-like
Caspase-like

Question 21

What occurs when a protein gets to the proteasome?

Answer 21

The ubiquitin must be removed before entry.

The protein must be stretched out by unfoldase.

Generates peptides 4-20 aa residues.

Question 22

The proteasome is located in the cytosol and the MHC molecules are made in the ER. How is this location problem solved?

Answer 22

TAP: Transporter associated with Antigen Processing

Transports peptides into the ER

Question 23

How do the peptides bind to Transporter associated with Antigen Processing (TAP)? What type of peptides can bind?

Answer 23

Tapasin is thought to tether the newly synthesized class I molecule to TAP to keep it close to incoming peptides.

Only peptides with 8-10 residues.

Question 24

What are the five steps of Class 1 MHC antigen processing and presentation? When does this process occur?

Answer 24

1. Proteins tagged (Ub)
2. Proteolysis of proteins ending in L, I, V, M
3. Delivery of peptide (selection for L, I, V, M enders)
4. Binding of peptides (chaperone-mediated)
5. Transport to the cell surface and presentation CD8 T cells

This is constitutive and happens regardless of whether foreign proteins are present.

Question 25

How does a T cell know whether it is seeing self or foreign peptide? What are the different outcomes?

Answer 25

During development we generate newborn T cells that can recognize everything including self peptide + MHC.

Then we eliminate T cells that:

1. recognize self peptide in complex with self-MHC binding tightly (negative selection)
2. have no affinity - T cell dies (death by neglect)
3. Weak/moderate affinity allows T cell to live an dleave the thymus and populate the periphery (positive selection)

Question 26

What is alloreactivity?

Answer 26

The reactivity of T cells (or B cells) to non-self MHC class I or II molecules (such as with allogenic graft rejection).

It’s possible that some of the positively-selected T cell receptors that bind weakly to self-MHC peptide may bind strongly to non-self MHC peptide and cause the killing of the T cell.

Question 27

What are the structural differnces between class I and class II MHC? What happens when no peptide is bound?

Answer 27

Class I has a light chain and a heavy chain.

Class II has II heavy chains.

If no peptide is bound, the MHC molecules fall apart.

Question 28

How do class I and class II molecules differ in the size of peptide they can hold?

Answer 28

Class I: 8-10 residues

Class II: 10-16 residues but can be up to 30+ because both parts of the molecule come together to grasp the peptide.

Question 29

What are the five main features of Class II presentation that makes it differ from class 1?

Answer 29

1. No tagging of proteins for destruction
2. Proteolysis of antigen into peptides mediated by lysosomal proteases
3. No topological barriers b/c peptides are on the same side of the membrane as class II molecule
4. Loading of peptides occurs in the endocytic compartment NOT on ER.
5. Peptides displayed to CD4 T cells in context of MHC class II.

Question 30

How do we get class II to the lysosome (since the default route is ER-golgi-PM) and how do we prevent peptides in the ER destined for Class I molecules from binding to class II molecules?

Answer 30

Invarient chain (Ii).

1. Scaffold/stabilizer
2. Barrier to peptides in the ER
3. Zip code to MHC class II compartment (MIIC) - ie the lysosome

Holds onto class II molecule so they can’t load onto class I.

Question 31

What is the structure of the invariant chain (Ii)? Where is it located?

Answer 31

Forms a trimer with 3 class II molecules and 3 invariant chains in the ER.

Question 32

What is the action of the invariant chain (Ii)?

Answer 32

1. Binds in the groove of MHC class II molecule
2. Ii cleaved to leave a fragment bound to the class II molecule and the membrane.
3. Further cleavage leaves short peptide fragment, CLIP, bound to the class II molecule within the groove.

Question 33

How does CLIP get out of the binding groove so an antigenic peptide can come in?

Answer 33

HLA-DM catalyzes the exchange between CLIP and antigenic peptide.

HLA-DM destabilizes peptide bound in the cleft.

Once dislodged, peptides with the right criteria for binding can bind in the groove and DM can “bump” peptide out until a peptide binds and fits so well that it can’t be bumped.

Question 34

When is the only time a class II molecule is without something in it’s peptide binding groove? What happens if there’s nothing in this groove?

Answer 34

When DM catalyzes peptide removal.

Without peptide in this groove, the class II molecule is destabilized, unfolds, and is destroyed by proteases in the lysosome.

Question 35

Class II molecules present antigens to what type of cell?

Answer 35

CD4 T cells.

Question 36

What are the specialized antigen presenting cells (APCs) that class II molecules are expressed on?

Answer 36

B cells, dendritic cells, and macrophages.

Question 37

Why is it that class I molecules are expressed on all nucleated cells and class II are expressed only on specialized antigen presenting cells (APCs)?

Answer 37

We have the potential to get a virus in all of our cells, which is why we need class I molecules everywhere.

Bacteria live in tissues and propagate extracellularly, which is why we need specialized antigen presenting cells.

Question 38

During a virus infection, _____ calls are important because they interact with MHC class I molecules which sample the inside of the cell.

Answer 38

CD8+ T cells

These are the ones that actually kill virus-infected cells.

Question 39

It take _____ days to generate an army of ____ that specifically recognize a new virus. Where does this type of cell first see a an antigen?

Answer 39

3-7 days

T-cells

First sees antigen in the draining node.

Question 40

What happens after initial infection with a virus? Explain the three steps that occur. What process is this describing?

Answer 40

1. Phagocytes engulf virus
2. Dendritic cells migrate to lymphoid organ and present antigen to virus-specific CD8+ T cells
3. If the particular CD8+ T cell can bind to the antigen/MHC class I complex it will become activated and proliferate.

This is cross-presentation or cross priming.

Question 41

How can an uninfected APC present viral peptides on class I molecules if the virus didn’t gain access to the cytosol and viral proteins are not being synthesized in the cytosol of the APC? Name three possibilities.

Answer 41

Possible that:

1. ER fuses with endosome or phagosome
2. Antigen crosses phagosome membrane into cytoplasm
3. ER-derived phagosomes contain TAP and export machinery.

Question 42

What location is the basis for adaptive immunity?

Answer 42

Lymph nodes and the spleen (ie are where the magic happens)

Question 43

What is needed to help eradicate a virus?

Answer 43

BOTH CD8+ and CD4+ T cells.

Question 44

Class I is for _____ peptides.

Class II is for _____ peptides.

What is the exception to this rule called? When does it occur.

Answer 44

Class I: cytosolic peptides
Class II: extracellular peptides

Class I can also present extracellular peptides through cross-presentation or cross-priming.

This occurs ONLY in dendritic cells.

Question 45

Why does it matter if cross-presentation happens?

Answer 45

Naive CD8+ T cells (CTLs -
ie cytotoxic T cells) must be activated by professional antigen presenting cells (APCs) - usually dendritic cells (DC).

CD8+ T cells need to see peptide in the context of class I MHC, not class II MHC.

Question 46

MHC I molecules are expressed on _______ while MHC class II molecules are expressed on _______.

Answer 46

Class I: all nucleated cells

Class II: only on specialized antigen-presenting cells

Question 47

MHC I molecules present peptides derived from ____ proteins to _____ T cells.

Answer 47

Cytosolic proteins.

CD8 T cells

Question 48

MHC II molecules present peptides derived from ________ or _________ proteins to _____ T cells.

Answer 48

Extracellular or intravesicular proteins.

To CD4 T cells.