Lecture 5- Dendritic cells Flashcards
Who discovered the dendritic cell?
Ralph M. Steinman.
Thought they may activate T cells.
They are the best antigen presenting cell at activating and programming naive t cells.
What are the 3 main types of dendritic cells?
- Conventional DCs:
Tissue resident, immature
2. Plasmacytoid DCs: Deal with viral infections. Secrete lots of class I interferon.
- Inflammatory DCs:
Recruited to tissues in response to infection. Monocyte derived. Can also migrate to lymph node and activate T cells.
What are the classes of conventional DCS? (classified by cell-markers they express)
- CD11Chi CD8alpha or lymphoid
- CD11Chi CD11b+ or myeloid
- CD11Chi CD103+ (enriched in e.g. Gut)
- Langerin+ DCs (skin)
What markers do dendritic cells express?
- Lost of cells express cd11c,not just DCs
- Zbtb46 seems to be unique to DCs
- DCs don’t tend to express CXCR1, which is on macrophages
Which are better at phagocytosis? DCs or macrophages?
Macrophages are much better than DCs at phagocytosis
What is unique about gut dendritic cells?
Food and commensal bacteria are not rejected in gut. But need to decide when pathogens are bad in gut.
Unique intestinal DCs
CD103+ DCs in the gut are able to drive “tolerance” to oral antigens from food and commensal bacteria.
Induce the generation of reg. T cells.
Dependent on TGF-beta and retinoic acid (a metabolite of vitamin A)
Structure of DCs?
Have long finger-like processes- dendrites.
high expression of costimulatory molecules e.g. CD80.
Chemokine receptors e.g. CCR5, CCR6.
Take up particulate/soluble antigens by endocytosis.
Many endocytic vesicles (contain MHC II and lysosomal proteins)
Where are DCs?
Immature DC migrate from bone marrow via blood to enter tissues.
In tissues they sample the environment and act as sensors for damage or infection.
Often found under surface epithelia.
What gives DCs the “licence” to mature?
Pattern Recognition Receptors
How do DCs take up antigen?
Many ways.
1. Take up liquid non-specifically -> macropinocytosis
- Also phagocytose via their:
complement R, FcR (bind antibody antigen complexes), C-type lectins e.g. mannose R, langerin - Some DCs express TLR7 and TLR9 and respond to viral infection.
Briefly, give some routes of Ag processing by DCs?
- Receptor-mediated phagocytosis
- Macro-pinocytosis
- Viral infection
- cross-presentation after phagocytic or macropinocytic uptake
- transfer from incoming dendritic cell to resident dendritic cell
What does the cross presentation pathway enable you to do?
Allows exogenous proteins to be presented by MHC I. (which is needed to switch on cd8 t cells)
This means that the APC does not need to be infected to present antigen.
Peptides from pathogens, infected dying cells, tumour cells.
So you’ve never had to actually become infected, you’ve recognised the viral cell
What is the licencing stage?
When we activate a response to pathogens via pattern recognition receptors (PRRs) like TLRs.
DAMPs e.g. uric acid or cytokins can also promote licencing.
What are DAMPs?
Danger Associated Molecular Patterns
What happens after licencing by the PRRs?
The TLR signalling induces changes in the dendritic cell. The most striking of which is changes in chemokine receptor expression.
CCR5 and CCR6 are downregulated and CCR7 is switched on.
CCR7 recognises a chemokine called CCL21 which allows DCs to go to the lymph nodes. Important!
What does CCR7 do?
(Why is it important that it’s switched on after pathogen induced licencing when TLR signalling alters DC chemokine receptor expression?)
CCR7 recognises a chemokine called CCL21 which allows DCs to go to the lymph nodes via lymph. Important!
What are the features of mature DCs migrating via lymph to lymphoid tissue?
- Express CCR7 (which recognises ccl21)
- Morphology changes- have very veiled strucutre.. membrane folds-> veils.
- Express very stable MHC/peptide complexes on their surface
- High levels of costimulatory molecules which allows them to have stable interaction with a T cell.
- They’re shit at taking up antigens now.
- High levels of long lived MHC molecules
- Attract Naive T cells
What is the process of switching a t cell on called?
Priming.
Present Ag to naive T lymphocytes.
Activate any antigen specific T cells to divide into effector cells that enter circulation
What does DC polarisation of T cells mean?
DCs tell T cells what to become.
E.g. Treg cell, th2 cell or whatever.
depends on environment (e.g. cytokines and parasites) what the DC tells the T cell to become.
What does IL12 promote?
Th1 cells
What does suppressed IL12 signal promote?
Th2 cells
What do secretary products from hookworm promote?
Treg cells- to dampen down immune response
What are the 3 main types of APC?
- Macrophages (via PRR)
- B cells (via BcR)
- Dendritic cells (via PRR)
Why are DCs such a special type of APC?
B cell and macrophages specialise in processing and presenting Ag from intracellular pathogens and soluble antigens.
DCs can process a wide range of antigens
Found in T cell areas of Lymph nodes.
Drive the initial clonal expansion and differentiation of naive T cell into effector cells.
Why are DCs the champion APC?
They are the only APCs adapted to PRIME NAIVE T cells!!!
