Pathogen-induced TLR signalling in immature dendritic cells induces their migration to lymphoid organs and enhances antigen processing Flashcards
Janeway seventh edition Chapter 8, pages 336-338
What stimulates an immature DC in peripheral tissues to become a mature DC that arrives in the PLO?
Not fully understood
TLR signalling plays a role
Signals from chemokines
What types of bacterial antigens stimulate TLRs and DEC 205 on DCs?
LPS and mannose residues
LPS and mannose residues stimulate what receptors on DCs?
TLRs and DEC 205
What does stimulation of TLRs or DEC 205 on a DC result in?
The DC becomes activated
Human cDCs express which TLRs?
All known TLRS except for TLR-9
What TLRs do plasmacytoid DCs express? (list 3.5)
TLR 9, TLR 1, TLR 7, and other TLRs to a lesser degree.
Other than TLRs, what types of DC receptors may contribute to DC activation? List two
Receptors that can bind pathogens, e.g. receptors for complement, and the mannose receptor.
What does DC TLR signalling result in?
Significant alteration in the chemokine receptors expressed by DCs.
What is the term for DC TLR signalling that results in significant alteration in the chemokine receptors expressed by DCs? Why?
“Licensing”, as the cells are now embarked on the program of differentiation that will enable them to activate T cells.
What specific receptor expression is induced on DCs by TLR signalling?
CCR7
What is the result of DCs expressing CCR7?
CCR7 makes the activated DCs sensitive to the chemokine CCL 21
What produces CCL21? What does CCL21 cause?
Lymphoid tissue produces CCL21 to induce migration through the lymphatics into local lymphoid tissues.
How do T cells enter PLOs? How do DCs enter PLOs?
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.
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?
Signals delivered by TLRs
TLR stimulation in a phagosome improves the efficiency of antigen processing from pathogens. How does this improve the immune response to pathogens?
This helps distinguish self from non-self and ensures an enhanced response to non-self antigens.
CCL21 signalling through CCR7 induces migration into lymphoid tissue. What else does CCL21 signalling through CCR7 induce?
Maturational changes in the DC, such that their phenotype is completely different on arrival in the T cell zone
Can a mature DC in lymphoid tissue engulf antigens by macropinocytosis or phagocytosis?
No
List 3 proteins a mature DC in lymphoid tissue express? What does this enable?
- 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.
- High levels of costimulatory B7
- High levels of adhesion molecules e.g. DC SIGN
What two structurally related transmembrane glycoproteins does the B7 costimulatory molecule represent?
B7.1 and B7.2
What chemokine do mature DCs secrete? What is its effect?
CCL18, this specifically attracts naive T cells.
Do DCs present self peptides? How is the immune system developed to maintain self tolerance? Give two examples
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.
Intracellular degredation of pathogens is thought to reveal pathogen components other than peptides that trigger dendritic cell activation. Give one example.
Bacterial or viral DNA containing unmethylated CpG dinucleotide motifs induces the rapid activation of pDCs, probably via TLR-9 recognition of the DNA
Where is TLR-9 found?
In the intracellular vesicles of pDCs
What pathways does DC exposure to bacterial DNA activate?
NFkappaB, and mitogen activated protein kinase (MAP kinase)
DC production of what is stimulated by the activation of the NFkappa B and MAP kinase pathways? (two classes, give examples)
Cytokines IL-6, IL-12, IL-18, and interferons IFN alpha and IFN gamma
What is the effect of IL-6, IL-12, IL18, IFN alpha and IFN gamma on the DC that produced them?
They augment expression of costimulatory molecules
Where are head shock proteins found, and what is their effect on DCs?
HSPs are an internal bacterial constituent that can activate the antigen presenting function of DCs.
How may some viruses be recognised by TLRs inside the DC?
By recognition of double stranded RNA from their replication
In all types of cells, what does viral infection stimulate the production of? What is the effect of this on DCs?
IFN alpha and IFN beta. These stimulate DCs to increase expression of co-stimulatory molecules.
Why are bacterial adjuvants needed as part of vaccines?
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.
What is induced by giving self proteins with bacterial adjuvants?
An auto immune response.
