Dendritic cells in tailored adaptive immunity

Question 1

What is the role of complement C3a in an infection?

Answer 1

1. Increase vascular permeability
2. Recruit leukocytes (Neutrophils)
3. Degranulation of Mast cells and Basophils

Question 2

What is the role of complement C3b in an infection?

Answer 2

1. Enhanced phagocytosis (via complement receptor - CR - binding)
2. Membrane attack complex (lysis of bacterial membrane)

Question 3

What is the three-signal-paradigm?

Answer 3

The three-signal-paradigm dictates that a T-cell needs a set of three sorts of signals to determine its function in an immune reaction.

Question 4

What is the first signal from a DC to a T-cell?

Answer 4

The first signal is when a DC presents a piece of antigen to a T-cell in order to activate its clonal expansion.

Question 5

What is the second signal from a DC to a T-cell?

Answer 5

The second signal from the DC is a co-stimulatory signal, which is needed in order to properly activate the T-cell. Without co-stimulation, the T-cell becomes anergic.

Question 6

Which receptors mediate the co-stimulation between DC and T-cell?

Answer 6

“CD80 / CD86” on the DC cell binds to “CD28” on the T-cell

Question 7

Describe the steps for antigen presentation by DC to T-cells.

Answer 7

1. Bacterial antigen binds to Toll-like receptors / PRR on DC
2. DC expresses it on MHC I or MHC II receptors
3. TCR binds to MHC receptors expressed with bacterial antigen
4. Co-stimulation between CD80/86 and CD28
5. Cytokine production by DC for T-cell specialization

Question 8

What is the third signal from a DC to a T-cell?

Answer 8

Cytokine production after PRR activation. This signal is needed for the differentiation of T-cells into specialized ones (Th1, Cytotoxic T-cell etc.)

Question 9

Why is the three-signal mechanism important in an immune response?

Answer 9

The three-signal mechanism can give rise to a diverse but selective array of T-cells which in turn is tailored to fight a very specific sort of pathogen which is infecting the body.

Question 10

What does PRR stand for?

Answer 10

Pattern Recognition Receptors

Question 11

What is the concept behind PAMP, DAMP, and SAMP?

Answer 11

The concept behind these terms is that dendritic cells are encoded to recognize certain patterns in order to distinguish between self, non-self, and danger.

Question 12

What receptors on dendritic cells activate what type of T-cells?

Answer 12

Endosomal antigen presented on MHC-II activates CD4+ T-cells and cytosolic proteins presented on MHC-I activate CD8+ T-cells.

Question 12

What receptors on dendritic cells activate what type of T-cells?

Answer 12

Endosomal antigen presented on MHC-II activates CD4+ T-cells and cytosolic proteins presented on MHC-I activate CD8+ T-cells.

Question 13

How do the multiple PRR variants influence the dendritic cell and its uptake of a pathogen?

Answer 13

Activation of various PRRs can dictate how the pathogen is being degraded and how the pathogenic protein is loaded onto the MHC receptors.

Question 14

What does a mature dendritic cell do?

Answer 14

It travels to the lymph nodes where it presents antigen on its MHC receptors to naive T-cells.

Question 15

What is the consequence of the multiple PRR variants and their activation sequence?

Answer 15

A pathogen can interfere with TLR activation, which in turn can lead to dendritic cells activating the wrong type of T-cells.

Question 16

What is CD28, where is it found and what is its specific function? (3 functions)

Answer 16

CD28 is a co-stimulatory receptor found on T-cells. Its functions are:
1. Lowering the activation threshold of TCR
2. Inducing proliferative genes in T-cells
3. It induces IL-2 production

Question 17

What other examples of co-stimulatory molecules are found on T-cells?

Answer 17

OX40, 4-1BB and CD27

Question 18

What is cross-presentation in dendritic cells?

Answer 18

Cross-presentation is when exogenous pathogenic material is presented on MHC-I receptors. Normally it would be presented on MHC-II.

Question 19

What is the function of TLR4?

Answer 19

TLR4 enhances cross-presentation.

Question 20

What do TLR2 and TLR4 signaling together induce?

Answer 20

TLR4 and TLR2 induce the production of transcription factor EB (TFEB). This in turn leads to rapid degradation of the phagosomes and prevents their content from being loaded onto MHC-I.

Question 21

What is the function of TLR9?

Answer 21

TLR9 prevents transcription factor EB from being produced. This leads to lesser degradation of the phagosomes, which makes them available for cross-presentation.

Question 22

What type of T-cell does delayed phagosomal degradation lead to?

Answer 22

Delayed phagosomal degradation leads to the activation of CD8+ T-cells. Delayed degradation can lead to cross-presentation which loads peptides on MHC-I. MHC-I receptors stimulate CD8+ T-cells.

Question 23

What main PRR families are found on a dendritic cell?

Answer 23

Toll-like receptors (TLR), NOD-like receptors (NLR), and RIG-1-like receptors (RLR).

(TLR is probably mentioned the most, though)

Question 24

What do activation and cooperation of multiple TLR variants result in?

Answer 24

Activation and cooperation of different variants of TLR can result in a more optimal innate immune response, which can react better and more specifically, depending on the type of pathogen.

Question 25

What is the function of IL-12, IL-6 and TNF-a?

Answer 25

They are all pro-inflammatory cytokines and dictate T-cell differentiation.

Question 26

What is the function of the IL-1 family and Type I interferons?

Answer 26

They cooperate with priming cytokines for the generation of T-cells.

Question 27

Where are RLR and cGAS receptors found? What is their function?

Answer 27

RLR and cGAS are receptors found in the cytosol of a dendritic cell. They are responsible for activating an immune response to viruses, which usually are inside the host cell.

Just like TLR and NLR on the surface, RLR and cGAS are on the inside.

Question 28

Where are TLR3, TLR7, TLR8, and TLR9 found? What kind of material do they react to? What other receptors react to the same material and where are they found?

Answer 28

These TLRs are found in endosomes and they react to nucleic acid. RLR and cGAS also react to nucleic acid, but those are found in the cytosol, instead of endosomes.

Question 29

What kind of pathogen leads to the production of INF-I and IL-1?

Answer 29

After the cytosolic invasion of virulent pathogens, or extensive tissue damage.

Question 30

Which interleukins are released after necrotic cell death?

Answer 30

IL-1 and IL-33.

Question 31

What are IRF3 and IRF7 important for?

Answer 31

Type I INF rely on signaling from these molecules. (IRF = interferon regulatory factor)

Question 32

Where do INF-I and IL-1 get produced?

Answer 32

These cytokines can virtually be produced by immune and non-immune cells. They are responsible for T-cell differentiation but need to work with other (priming) cytokines.

They activate differentiation but other cytokines make T-cells more specific.

Question 33

Why could the in-vitro cellular reaction to cytokines be different than in-vivo?

Answer 33

During a real infection in-vivo, DCs produce a cocktail of different cytokines which can lead to a different reaction than when only one cytokine is used during in-vitro experiements.

Question 34

Which cytokines drive Th1, Th2, Th17, and Treg differentiation?

Answer 34

Th1 driven by IL-12
Th2 driven by IL-4
Th17 driven by a combination of IL-6 and TGF-b
Treg is driven by TGF-b (in the absence of infection)

Question 35

Give an example of three priming cytokines. What other non-priming cytokine does it synergize with for the generation of protective immunity?

Answer 35

IL-6, IL-12, and IL-4

They often synergize with IL-1.

Question 36

Why is IL-1 under heavy regulation?

Answer 36

Because it has a highly inflammatory nature. It is one of the T-cell differentiation inducers.

Question 37

What kind of pathogen leads to INF-I production?

Answer 37

Viral pathogens lead to Type I Interferon production.
They are also involved in CD8+ T-cells. This makes sense, as CD8+ T-cells are responsible for killing virus-infected cells.

Question 38

What does INF-I induce, when there is no TCR response and why?

Answer 38

INF-I alone induces a pro-apoptotic reaction in T-cells. That may be so to prevent the activation of bystander T-cells.

Question 39

Why can an INF-I-focused vaccine be challenging to develop?

Answer 39

Because one must be aware of the various interactions between INF-Is and other molecules, leading to pathogen-specific reactions.

Question 40

Why is the initial location of the infection the tissue important for protective immunity?

Answer 40

Because some infections can be contained within the tissue, with no need to alert the whole body. Systemic infections can lead to the activation of the whole-body immune system. Previous infections can also influence how the body would react to new infections.

Question 41

What factors lead to tissue-specific immunity?

Answer 41

DC populations which are unique to the tissue they are in and their ability to produce specific cytokines.

Question 42

What kind of T-cells would DCs in the gut induce?

Answer 42

Mostly regulatory (Treg) and mucosal (Th17) T-cells.
That is because the gut is exposed to a bacterial microbiome and the body must not constantly react to them.

Question 43

Name two ways in which a previous infection can lead to a different reaction to a new pathogen

Answer 43

1. Some pathogens can promote regulatory and anti-inflammatory cytokines, lowering the overall reaction to a new pathogen.
2. In the case of co-infection, one pathogen may lead to the production of one set of pathogen-specific cytokines, while the other co-infecting pathogen may remain unaffected.

Question 44

How do commensal microbiota prevent an immune reaction?

Answer 44

The immune reaction on the commensal flora is inhibited by short-chain fatty acids (SCFA).
These are metabolic products of the gut microbiota

Question 45

What does butyrate do in the gut?

Answer 45

It downregulates LPS-induced pro-inflammatory cytokine production (IL-6, IL-12).