L8 - Dendritic cells and initiation of immunity Flashcards
Dendritic cells: what are they, what do they do, what key features do they have, and how do they navigate the body?
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
Can T-cells activate by themselves?
No, they require dendritic cells to activate them as APCs
Dendritic cells: what types are there?
- Classical or Conventional DCs (cDC)
- Plasmacytoid DCs
- Monocyte Derived DCs (also known as Inflammatory DCs)
- Langerhans cells
Classical/conventional DCs (cDC): where does they reside and what subsets are there?
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
Plasmacytoid DCs: what are they, what do they secrete, what do they express, and how good are they at activating Naive T-cells?
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
Monocyte Derived DCs (also known as Inflammatory DCs): what do they do, where are they derived from, and what do they rely on?
Recruited to tissues in response to infection - variety of roles e.g. supporting effector T cells
Monocyte-derived
- M-CSF and CCR2 dependent
Langerhans cells: where are they found, what do they do, and where do they self-renew?
In skin
It is more similar to macrophages but has some functional overlap with cDC
Self renew in tissue
Intestinal dendritic cells
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
cDCs in normal tissue
- 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)
Immature dendritic cells: what do they do
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
Routes of antigen presentation from dendritic cells
- Receptor-mediated phagocytosis
- Macro-pinocytosis
- Viral infection
- Cross presentation after phagocytic or macropinocytic uptake
- Transfer from incoming dendritic cell to resident dendritic cell
Receptor-mediated phagocytosis: what type of pathogens are presented, what MHC molecules are loaded, and what type of naive T-cell is activated?
Extracellular bacteria
MHC class II
CD4 T-cells
Macro-pinocytosis: what type of pathogens are presented, what MHC molecules are loaded, and what type of naive T-cell is activated?
Extracellular bacteria, soluble antigens, viral particles
MHC class II
CD4 T-cells
Viral infection: what type of pathogens are presented, what MHC molecules are loaded, and what type of naive T-cell is activated?
Viruses
MHC class I
CD8 T-cells
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?
Viruses
MHC class I - (initially taken up by class II but gets presented as class I)
CD8 T-cells
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?
Viruses
MHC class I
CD8 T-cells
Antigen capture process of dendritic cells
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
DC maturation: the process
- 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
Mature DCs: how do their properties differ from immature DCs?
- 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’)
Multiple Factors Impact Immune Polarisation
Leccy or ignore
APCs: what are they, what are the three main groups, how are they activated, and what antigens do they specialise in displaying?
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
DC vaccines: what generations are there and what do they do?
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
