M: Adaptive immunity 3 - Week 5/6

Question 1

In addition to the binding of the peptide antigen-MHC complex by the TCR, are there any other signals required for full effector activation? What are these signals called?

Answer 1

Yes. They are called “Co-stimulatory signals”

Question 2

What are the 3 signals required for full activation of the naive T cells?

Answer 2

Signal 1: TCR recognises antigen on MHC molecule
Signal 2: “Co-stimulation” for T cell expansion
Signal 3: Induction of T cell differentiation

Question 3

In order to effectively activate naive CD4 and CD8 T-cells, what must an APC do? (2)

Answer 3

1. Acquire and process antigen in compartments which gain access to MHC Class I and II pathways AND
2. Interact with naive T cells to induce effector T cells

Question 4

How do APCs interact with naive T cells to induce effector T cells? (5)

Answer 4

1. they locate appropriate T cells (in the secondary lymphoid tissue)
2. then they adhere to the T cells
3. Present MHC associated peptides to T cells [signal 1]
4. Provide “co-stimulation” [signal 2] for T cell expansion
5. Induce T cell differentiation [signal 3]

Question 5

What cells are the best antigen presenting cells (APCs)?

Are these cells a good stimulator of naive T cells?

Answer 5

Dendritic cells. They are the best equipped to activate naive T cells

No they are not.

Question 6

What is the final outcome of the dendritic cell maturation pathway?

Answer 6

The activation of both CD4 and CD8 T cells

Question 7

In regards to Dendritic Cells:
A) How efficient are they at capturing antigen?
B) What do they do in normal, non-inflamed tissue?
C) How much MHC II do DCs express in non-inflamed tissue?
D) What do DCs secrete? What does this achieve?

Answer 7

A: Very. However are poor stimulators of naive T cells
B: They constantly sample their surrounding environment for antigen (through multiple mechanisms)
C: Low level of MHC II on plasma membrane
D: TGF-beta - helps to suppress induction of strong immune responses

Question 8

Why is migration of dendritic cells to the draining lymph nodes restricted in normal non-inflamed tissues?

Answer 8

T cells become activated in the lymph nodes. During infection, the DCs will migrate to the draining lymph nodes to activate the T cells.

In non-inflamed tissue, we don’t want to activate T cells when there is no need, so migration to these draining lymph nodes is restricted.

Question 9

Where can Pattern Recognition Receptors (PRRs) be displayed? (3)

Answer 9

Locations include:
- surface of our cells
- cystolic compartments
- endosomic compartments

*depends on the PRR, some are displayed on surface of cells, some in cytosolic etc.

Question 10

True/False: All TLRs form hetero-dimeric molecules

Answer 10

False. Only some. For example TLR 2 and 6 form a hetero dimer with each other, as well as TLR 1 and 2 forming a hetero dimer with each other

Question 11

What initiates DC maturation?

Answer 11

DC binding to pathogens

Question 12

What type of signalling induces DC maturation?

Answer 12

PRR signalling
- PAMPs on pathogens ligate the PRR on the DCs and stimulates their maturation

Question 13

List the series of maturation events that the DC undergoes once bound (7)

Answer 13

1. Migration of DC to draining lymphoid tissue
2. Increased antigen processing
3. Increased surface expression of MHC I and II
4. Increased surface expression of adhesion molecules
5. Increased expression of co-stimulatory molecules (CD80, CD86)
6. Increased secretion of cytokines
7. Maturing DCs lose their capacity to capture antigen but are now able to activate T cells

Question 14

How do DCs migrate to the draining lymphoid? (2)

Answer 14

• via the lymphatics (conjunctiva) or
• spleen via blood (if intraocular)

Question 15

Why are the adhesion molecules important for binding of APC to T cell?

Answer 15

they allow the LFA1 on the T cell to bind to the adhesion molecule on the DC - resulting in these 2 cells staying tightly connected for quite some time

Question 16

What does “co-stimulation” require?

Answer 16

interaction between the molecule expressed on the T cells (known as CD28, CD80, CD86) on those activated APCs

Question 17

Name 2 examples of co-stimulatory molecules that licensed DCs display

Answer 17

• CD80
• CD86

Question 18

What does the induction of CD80 and CD86 on the DC enable activation of?

Answer 18

antigen specific CD4 T cells

Question 19

On receiving signal 1 and 2, describe what happens to the CD4 T cell? (3)

Answer 19

• it now expresses CD40L
• and expresses IL-2R, secretes IL-2 and now proliferates
• differentiates [signal 3] to perform its effector function

Question 20

What do activated CD4 T cells differentiate into based on the following conditions:
A) Early in infection
B) As infection persists
C) Worm/Helminth infection

Answer 20

A: Early in infection there is lots of IL-6 and TGFbeta cytokines produced by APC that drive differentiation into TH17. IL-6 also drives differentiation into TFH
B: IL-12, IL-18, and IFN-y produced by APC drives differentiation into TH1
C: IL-4 and IL-33 produced by APC drives differentiation into TH2

Question 21

When there is a lot of TGF-beta produced by APCs (i.e. in steady state, normal conditions), what are CD4 T cells driven to differentiate into?

Answer 21

Regulatory T cells (Treg)

Question 22

Describe TH17. What do they produce? (2) What does this achieve? (1)

Answer 22

characterised by production of IL-6 and IL-17, which helps with the recruitment of neutrophils to the site of infection

Question 23

Describe TFH. what does TFH stand for and what do TFH cells do?

Answer 23

Follicular Helper Cells. Help with B cell proliferation and differentiation and thus the antibody response

Question 24

Describe TH1. what do they produce? (2) What do they achieve? (2) What are they involved in? (1)

Answer 24

characterised by production of IFN-y and TNF. TH1 cells are very efficient at fully activating macrophages and also help B cells produce particular types of antibodies (IgG)

They are involved in the inflammation response during tissue damage

Question 25

Describe TH2 cells. What are they involved in (2) and what are they responsible for the activation of? (3)

Answer 25

responsible for activation of mast cells, eosinophils and activate antibodies such as IgE
- are involved in parasitic immunity, allergy

Question 26

What do Treg cells do?

Answer 26

Regulate immune responses

Question 27

Describe the 6 steps involved in the activation and action of CD8 T-cells

Answer 27

1. APC is activated when PAMPs bind PRR
2. APC migrates to lymph nodes via lymphatics
3. In lymphatics, APC upregulates costimulatory and adhesion molecules
4. APC processes the internalised cystolic antigen and presents them as peptides on MHC class I
5. In lymph node, MHC Class I molecule binds to CD8 T-cell receptor and the costimulatory molecules will bind as well – resulting in proliferation and activation of CD8 T cell
6. CD8 T cells will then migrate from lymph node to the infected tissue to kill the infected cells

Question 28

How can CD4 T cells and B cells provide help for each other? (3) (remember the 3 points at bottom of flash card)

Answer 28

• an activated CD4 T cell can become a helper to the B cell
• Once a B cell receives a signal from the activated CD4 T cell, this is when ISOTYPE SWITCHING, AFFINITY MATURATION and MEMORY RESPONSES occur
• The CD4 T cell will bind and interact with the B cell

So, the interaction provides the signals needed for:
- isotype switching , - affinity maturation, - memory responses

Question 29

How are antigens that bind to the B cell receptor internalised?

Answer 29

By receptor mediated endocytosis

Question 30

Can B cells act as APCs?

Answer 30

Yes

Question 31

Describe the interaction between CD4 T cells and B cells in 6 steps

Answer 31

1. activated T cells express CD40L
2. activated CD4 T cells secrete IL2 and ILR2 and other appropriate cytokines, such as TGF-beta, TFG, IFNy and IL-4, all which act on the B cell
3. B cells present their internalised antigens on their MHC class II, to the TCRs
4. B cell CD40 also binds to T cell CD40L
5. Result is the B cell now prollferates, isotype switching and affinity maturation
6. B cells also secrete their antibodies and differentiate into memory B cells (well some of them)

Question 32

True/False: CD80 and CD86 are consitutively expressed on APCs

Answer 32

False. They are NOT consitutively expressed (or only weakly expressed) on APCs

Question 33

True/False: CD40L is not constitutively expressed on T cells

Answer 33

True

Question 34

Does a T cell have to be activated to express CD40L?

Answer 34

Yes

Question 35

Once activated, what do activated effector T and B cells do? (4)

Answer 35

• leave lymphoid tissue
• home to site of inflammation
• migrate to inflammatory site
• perform effector function

Question 36

TH17 cells release IL-17. What does IL-17 activate? (3)

Answer 36

• fibroblasts
• epithelial cells
• keratinocytes

Question 37

What do TH17 cells release to induce production of defensins from keratinocytes? (hint: it’s an interleukin)

Answer 37

IL-22

Question 38

What does IL-17 induce epithelial cells to do/release? (4)

Answer 38

Induces them to release IL-6, CXC8, GCSF, GMCSF, which are inflammatory cytokines, chemokines that act on the bone marrow to produce and release more neutrophils and monocytes (macrophages)

Question 39

What can we use to inhibit T cell activation? (3)

Answer 39

1. Immunosuppresive drugs (e.g. cyclosporine/tacrolimus)
   - can inhibit IL-2 production and T cell proliferation
2. Antibodies (e.g. anti-CD3)
   - block T and PC, T cells and B cell molecular interactions
3. Soluble ligands (e.g. CD40L, CTLA4)
   - blocks costimulatory interactions