Dendritic Cells Flashcards
1
Q
Role of dendritic cells
A
- Innate immune cells - but play a role in the start of adaptive immunity
- Sample environment - capture antigens and present them to T cells
- Important in vaccines - inject antigens + signals that activate DCs
2
Q
Properties of immature DCs
A
- Peripheral tissue - non-secondary lymphoid tissue
- Skin and mucosa - pathogens most concentrated
- Very good at antigen capture - very bad at antigen presentation
- Need innate danger signal to mature - and migrate
3
Q
Properties of mature DCs
A
- Secondary lymphoid tissue
- Come into contact with naive T cells
- Good at antigen presentation and co-stimulation
- Naive T cell requires: antigen to be presented to them AND co-stimulatory molecules
- Proliferate and mount adaptive immune response
4
Q
Capture and uptake of antigens - 3 endocytic pathways
A
- Macropinocytosis
- Receptor mediated pathway
- Phagocytosis
5
Q
Macropinocytosis - antigen capture
A
- Non specific - involves uptake of fluid from surroundings
- Formation of large membrane bound vesicles
- Projections from cell surface - called ruffles - encapsulate material - allows DC to capture molecules dissolved/ suspended in the extracellular fluid
- No need for receptors - capture anything in that fluid
- Constantly sampling environment using macropinocytosis
- Hence uptaking antigens from surroundings
6
Q
Receptor mediated pathway - antigen capture
A
- DCs express an array of receptors - which capture molecules
- Receptors function in receptor mediated endocytosis and phagocytosis
E.g., C-type lectins, Fc receptors, Scavenger receptors, Receptors for heat shock proteins etc
7
Q
Phagocytosis - antigen capture
A
- Receptor mediated uptake of large particulate species - e.g., bacteria, gram+ cocci, yeast cells, apoptotic bodies etc
8
Q
Direct signals - to trigger DC maturation
A
- TLRs- DCs have TLRs that recognise an array of microbial molecules - e.g., TLR2 - gram+ bacterial cell wall compounds
- Recognition causes activation
- Molecules recognised by TLRs are only present when there is infection
9
Q
Indirect signals - DC maturation
A
- Molecule secretion triggered by pathogens or response to tissue damage - e.g., macrophages
- Tumor necrosis factor-alpha
- Interleukin - 1- beta
- Prostaglandin E2
10
Q
Migration of DCs
A
- DCs migrate from peripheral tissues - to lymph nodes
- They home into sites where T cell concentration is highest - to present antigen to them
- Danger signal - into afferent lymphatic tissue - into lymph nodes (secondary lymphoid tissue)
- Dendrites - projections on cell surface of DC - allows DCs to interact with multiple T cells at once
11
Q
Receptors involved in migration of DCs - (3 receptors)
A
- Langerhans cells - interact with keratinocytes - via E-cadherin - expression of E-cadherin is reduced upon maturation
- Chemokine receptor 7 - (CCR7) - expression increased upon maturation - enables homing to lymph nodes
- CCR7 - has two ligands - molecules that are recognised by the chemokine receptor
- First uses: CCL21 - expressed by endothelial cells of lymphatic vessels - from skin to lymphatic vessels
- Once DC enters lymph node - DC follows gradient of CCL19 - expressed by stroll cells in T cell zone of lymph nodes - where T cells are concentrated
12
Q
What type of cells do DCs present antigens to?
A
- CD4+ T cells (MHC Class 2)
- CD8+ T cells (MHC Class 1)
13
Q
How is antigen presentation regulated?
A
- By maturation of DCs
- Enhanced when DCs become mature - much better at antigen presentation
14
Q
Properties of MHC Class 2 molecules
A
- Synthsized in ER
- Alpha and Beta chain
- Have invariant chain - important as it blocks the MHC class 2 binding site in ER + signals MHC class to be packaged into MIIC (endocytic compartment)
15
Q
Antigen presentation - MHC class 2
A
- MHC2 molecules are synthesised in ER and enter the MIIC and the invariant chain is chopped up by proteases - opens up peptide binding groove of MHC2 molecules
- Antigens have been taken up by cell- are taken into MIIC and chopped up (antigen proteolysis) and then bind to MHC2 molecules
- These are then displayed on the cell surface to T cells
16
Q
Function of the invariant chain?
A
It blocks the MHC class 2 binding site in ER + signals MHC class to be packaged into MIIC (endocytic compartment)
- Means MHC2 doesn’t bind to free peptides in the ER that are for MHC1 molecules - and only binds when inside the MIIC
17
Q
How is antigen presentation switched off in immature DCs?
A
- Low activity of vacuolar proton pump = high pH = low protease activity - so inefficient at chopping up invariant chain
- High levels of cystatin C - prevent cleavage of invariant chain to cathepsin S - (which also helps chop up invariant chain)
- Cell surface MHC2 molecules are rapidly endocytosed
18
Q
How is antigen presentation turned on in mature DCs?
A
- High activity of vacuolar proton pump = low pH = higher protease activity = more efficient chopping of invariant chain
- Low levels of cystitis C - allows cleavage of cathepsin S = more efficient chopping of invariant chain
- Limited endocytosis of MHC2 molecules from surface of cell
- Increase in synthesis of MHC2 molecules by cell
19
Q
Classical MHC1 pathway?
A
- Antigens in cell are processed by proteasome into peptides and translocated to the TAP on ER
- Peptides bind with folded MHC1 molecules
- Peptide loaded MHC1 molecules are transported to Golgi and then to the surface
20
Q
Expression of MHC1 molecules in immature/mature DCs
A
- MHC1 pathway is not switched off in immature DCs
- But there is a higher level of expression in mature DCs
- Because there is constant protease activity in the proteasome of the cell
21
Q
What is cross presentation and why is it important for DCs?
A
- Is presenting antigens from outside of the cell on MHC1 molecules - exogenous antigens - intersect with MHC1 pathway
- DCs still need to present antigens - adaptive immune response against intracellular pathogens that don’t infect DCs
- E.g., measles don’t infect DCs but DCs still present antigens on MHC1 molecules - very important in antiviral immunity
22
Q
What co-stimulatory molecules are help T cell activation?
A
- B7.1 and B7.2 - transduced by CD28 (on T cell)
- Mature DCs express B7.1 and B7.2 on cell surface - recognised by CD28
- Combination of antigen + CD4/CD8 and B7.1/B7.2 + CD28 to trigger the activation of T cells
23
Q
What happens after T cell activation?
A
- Proliferation of effector cells
