Pathogen-induced TLR signalling in immature dendritic cells induces their migration to lymphoid organs and enhances antigen processing

Question 1

What stimulates an immature DC in peripheral tissues to become a mature DC that arrives in the PLO?

Answer 1

Not fully understood
TLR signalling plays a role
Signals from chemokines

Question 2

What types of bacterial antigens stimulate TLRs and DEC 205 on DCs?

Answer 2

LPS and mannose residues

Question 3

LPS and mannose residues stimulate what receptors on DCs?

Answer 3

TLRs and DEC 205

Question 4

What does stimulation of TLRs or DEC 205 on a DC result in?

Answer 4

The DC becomes activated

Question 5

Human cDCs express which TLRs?

Answer 5

All known TLRS except for TLR-9

Question 6

What TLRs do plasmacytoid DCs express? (list 3.5)

Answer 6

TLR 9, TLR 1, TLR 7, and other TLRs to a lesser degree.

Question 7

Other than TLRs, what types of DC receptors may contribute to DC activation? List two

Answer 7

Receptors that can bind pathogens, e.g. receptors for complement, and the mannose receptor.

Question 8

What does DC TLR signalling result in?

Answer 8

Significant alteration in the chemokine receptors expressed by DCs.

Question 9

What is the term for DC TLR signalling that results in significant alteration in the chemokine receptors expressed by DCs? Why?

Answer 9

“Licensing”, as the cells are now embarked on the program of differentiation that will enable them to activate T cells.

Question 10

What specific receptor expression is induced on DCs by TLR signalling?

Answer 10

CCR7

Question 11

What is the result of DCs expressing CCR7?

Answer 11

CCR7 makes the activated DCs sensitive to the chemokine CCL 21

Question 12

What produces CCL21? What does CCL21 cause?

Answer 12

Lymphoid tissue produces CCL21 to induce migration through the lymphatics into local lymphoid tissues.

Question 13

How do T cells enter PLOs? How do DCs enter PLOs?

Answer 13

T cells cross the high endothelial venule wall to leave the blood and reach the T cell zone. DCs enter via afferent lymphatics and migrate directly into the T cell zones from the marginal sinus.

Question 14

Pathogens that enter the immature dendritic cell via phagocytosis are processed in the endocytic compartment for presentation by MHC class II molecules. What increases the efficiency of antigen processing by the endocytic compartment?

Answer 14

Signals delivered by TLRs

Question 15

TLR stimulation in a phagosome improves the efficiency of antigen processing from pathogens. How does this improve the immune response to pathogens?

Answer 15

This helps distinguish self from non-self and ensures an enhanced response to non-self antigens.

Question 16

CCL21 signalling through CCR7 induces migration into lymphoid tissue. What else does CCL21 signalling through CCR7 induce?

Answer 16

Maturational changes in the DC, such that their phenotype is completely different on arrival in the T cell zone

Question 17

Can a mature DC in lymphoid tissue engulf antigens by macropinocytosis or phagocytosis?

Answer 17

No

Question 18

List 3 proteins a mature DC in lymphoid tissue express? What does this enable?

Answer 18

1. Very high levels of long-lived MHC class I and MHC class II molecules. This enables them to stably present peptides already taken up and processed.
2. High levels of costimulatory B7
3. High levels of adhesion molecules e.g. DC SIGN

Question 19

What two structurally related transmembrane glycoproteins does the B7 costimulatory molecule represent?

Answer 19

B7.1 and B7.2

Question 20

What chemokine do mature DCs secrete? What is its effect?

Answer 20

CCL18, this specifically attracts naive T cells.

Question 21

Do DCs present self peptides? How is the immune system developed to maintain self tolerance? Give two examples

Answer 21

Yes, but:

• the T cell receptor repertoir is purged of self-peptide recognition during development in the thymus
• Mature tissue DCs presenting self-peptide that reach the end of their life without activation travel via lymphatics to PLOs, where they induce anergy in any T cell that recognises them, because they lack costimulatory molecules.

Question 22

Intracellular degredation of pathogens is thought to reveal pathogen components other than peptides that trigger dendritic cell activation. Give one example.

Answer 22

Bacterial or viral DNA containing unmethylated CpG dinucleotide motifs induces the rapid activation of pDCs, probably via TLR-9 recognition of the DNA

Question 23

Where is TLR-9 found?

Answer 23

In the intracellular vesicles of pDCs

Question 24

What pathways does DC exposure to bacterial DNA activate?

Answer 24

NFkappaB, and mitogen activated protein kinase (MAP kinase)

Question 25

DC production of what is stimulated by the activation of the NFkappa B and MAP kinase pathways? (two classes, give examples)

Answer 25

Cytokines IL-6, IL-12, IL-18, and interferons IFN alpha and IFN gamma

Question 26

What is the effect of IL-6, IL-12, IL18, IFN alpha and IFN gamma on the DC that produced them?

Answer 26

They augment expression of costimulatory molecules

Question 27

Where are head shock proteins found, and what is their effect on DCs?

Answer 27

HSPs are an internal bacterial constituent that can activate the antigen presenting function of DCs.

Question 28

How may some viruses be recognised by TLRs inside the DC?

Answer 28

By recognition of double stranded RNA from their replication

Question 29

In all types of cells, what does viral infection stimulate the production of? What is the effect of this on DCs?

Answer 29

IFN alpha and IFN beta. These stimulate DCs to increase expression of co-stimulatory molecules.

Question 30

Why are bacterial adjuvants needed as part of vaccines?

Answer 30

Because many foreign antigens are insufficient to induce an immune response on their own, and require bacterial adjuvants to induce expression of co-stimulatory molecules.

Question 31

What is induced by giving self proteins with bacterial adjuvants?

Answer 31

An auto immune response.