L8 - Dendritic cells and initiation of immunity

Question 1

Dendritic cells: what are they, what do they do, what key features do they have, and how do they navigate the body?

Answer 1

Antigen-presenting cells (APC)

The best APC at activating and programming, activating naive T cells - sample tissue environment and act as damage/sensor infection

Have long finger-like processes

Immature DC migrate from bone marrow via blood to enter tissues

Question 2

Can T-cells activate by themselves?

Answer 2

No, they require dendritic cells to activate them as APCs

Question 3

Dendritic cells: what types are there?

Answer 3

• Classical or Conventional DCs (cDC)
• Plasmacytoid DCs
• Monocyte Derived DCs (also known as Inflammatory DCs)
• Langerhans cells

Question 4

Classical/conventional DCs (cDC): where does they reside and what subsets are there?

Answer 4

Tissue-resident

cDC1 and cDC2 subsets

cDC1:
* BATF3 or IRF8 dependent
* Good at cross-presentation to CD8+ T cells
* Express CD8aa, DEC-205 or CD103
* Produce more IL-12 than cDC2s
* Express e.g. Toll-like receptor 3 (TLR3) i.e. viral recognition

cDC2:
* IRF4 dependent
* Prime naïve T cells
* Associated with a variety of CD4+ TH cell responses
* Express CD11b, DC immunoreceptor 2 (DCIR2), CD301b (MGL2), CD4 or signal regulatory protein-α (SIRPα)
* Can be difficult to distinguish from MoDCs and other DCs induced during inflammation

Question 5

Plasmacytoid DCs: what are they, what do they secrete, what do they express, and how good are they at activating Naive T-cells?

Answer 5

Sentinels for viral infections

Secrete large amounts of class I interferon

Express intracellular PRR TLR7 and TLR9 (eg viral recognition)

Less effective at priming naïve T cells

Question 6

Monocyte Derived DCs (also known as Inflammatory DCs): what do they do, where are they derived from, and what do they rely on?

Answer 6

Recruited to tissues in response to infection - variety of roles e.g. supporting effector T cells

Monocyte-derived

• M-CSF and CCR2 dependent

Question 7

Langerhans cells: where are they found, what do they do, and where do they self-renew?

Answer 7

In skin

It is more similar to macrophages but has some functional overlap with cDC

Self renew in tissue

Question 8

Intestinal dendritic cells

Answer 8

CD103+ DCs in the gut are able to drive “tolerance” to oral antigens from food and commensal bacteria

Induce the generation of regulatory T cells

Dependent on TGFb and retinoic acid (a metabolite of vitamin A)

We see this type of DC enriched in the gut where they appear to drive regulatory and anti-inflammatory responses so likely play a role in preventing in appropriate activation

Question 9

cDCs in normal tissue

Answer 9

• Immature
• Many dendrites - antigen capture, migration?
• Low expression of costimulatory molecules e.g. CD80, CD86
• Chemokine Receptors e.g. CCR5, CCR6
• Take up particulate/soluble antigens by endocytosis
• Many endocytic vesicles (contain MHC II and lysosomal proteins)

Question 10

Immature dendritic cells: what do they do

Answer 10

Have antigen-capture machinery for processing antigens

Immature DCs are often found under surface epithelia - capture antigens quickly upon infection

Very active in ingesting antigens by phagocytosis using

e.g. complement receptors, FcR, C Type Lectins eg DEC205, Langerin Dectin 1

Other extracellular antigens taken up by macropinocytosis-

- lots of fluid taken up

- good for pathogens that can evade conventional phagocytosis

Viral infection into cytosol – peptides presented via MHC I

Question 11

Routes of antigen presentation from dendritic cells

Answer 11

• Receptor-mediated phagocytosis
• Macro-pinocytosis
• Viral infection
• Cross presentation after phagocytic or macropinocytic uptake
• Transfer from incoming dendritic cell to resident dendritic cell

Question 12

Receptor-mediated phagocytosis: what type of pathogens are presented, what MHC molecules are loaded, and what type of naive T-cell is activated?

Answer 12

Extracellular bacteria

MHC class II

CD4 T-cells

Question 13

Macro-pinocytosis: what type of pathogens are presented, what MHC molecules are loaded, and what type of naive T-cell is activated?

Answer 13

Extracellular bacteria, soluble antigens, viral particles

MHC class II

CD4 T-cells

Question 14

Viral infection: what type of pathogens are presented, what MHC molecules are loaded, and what type of naive T-cell is activated?

Answer 14

Viruses

MHC class I

CD8 T-cells

Question 15

Cross presentation after phagocytic or macropinocytic uptake: what type of pathogens are presented, what MHC molecules are loaded, and what type of naive T-cell is activated?

Answer 15

Viruses

MHC class I - (initially taken up by class II but gets presented as class I)

CD8 T-cells

Question 16

Transfer from incoming dendritic cell to resident dendritic cell: what type of pathogens are presented, what MHC molecules are loaded, and what type of naive T-cell is activated?

Answer 16

Viruses

MHC class I

CD8 T-cells

Question 17

Antigen capture process of dendritic cells

Answer 17

DCs capture pathogens by phagocytic receptors or micropinocytosis etc, after being activated by:

• PAMPS
• PRRs (TLRs)
• DC-SIGN recognises mannose, fucose on pathogens
• Dectin-1: recognises b 1,3, glucans in fungal cell walls

Receptors for complement

• Complement R
• FcR (bind antibody-antigen complexes)
• C-type Lectins e.g. Mannose R, DEC205, langerin (skin), dectin-1

Responses to the pathogens are then activated

Question 18

DC maturation: the process

Answer 18

• Triggered by PAMPs - result in PRR activation (essential to ‘license’ DC maturation)
• TLRs get activated and induce CCR7
• CCR7 enhances processing of pathogen-derived antigens
• CCR7 augments expression of co-stimulatory molecules and MHC molecules
• Mature dendritic cell in T-cell zone primes naive T-cells

Question 19

Mature DCs: how do their properties differ from immature DCs?

Answer 19

• High levels of costimulatory molecules - e.g. CD80, CD86
• Stop taking antigen up - Poorly endocytic
• High levels of long-lived MHC molecules
• Attract Naive T cells
• Express high levels of adhesion molecules
• Express high levels of very stable MHC/peptide complexes
• Secrete CCL18
• Express CCR7
• Have membrane folds (‘veils’)

Question 20

Multiple Factors Impact Immune Polarisation

Answer 20

Leccy or ignore

Question 21

APCs: what are they, what are the three main groups, how are they activated, and what antigens do they specialise in displaying?

Answer 21

Antigen-presenting cells, there are three main groups but DC are the main ones involved in initiating an immune response while the other two are better at propagating an immune response by supporting already primed T-cells

• Macrophages - PRRs, intracellular/soluble
• B cells - BcR, intracellular/soluble
• Dendritic cells - PRRs, wide variety

Question 22

DC vaccines: what generations are there and what do they do?

Answer 22

First-generation DC vaccines
* immature patient-isolated natural DCs or ex vivo-generated mo-DCs
* Loaded with synthetic antigen or tumor cell lysates
* limited success but established safety

Second-generation DC vaccines
* Matured mo-DCs
* More refined methods of antigen prep.
* Better performance clinically

Next-Generation DC Vaccines
* Focuses on use of specific subsets of naturally occurring DCs
* Initial trials look to be safe AND more effective