Lecture 3 Flashcards
Why was it difficult for Steinman to convince people dendritic cells were a different type of cell rather than a subset of macrophages?
Both express markers such as CD11c and F4/80
Both express MCH II
Both phagocytic
Both sensors - have receptors on their membrane to recognise foreign material
What is the function of macrophages?
Clear up necrosis, infected cells, bacterial infection.
They destroy pathogen
Induce inflammatory response
Remain in tissue where pathogens are
What is the function of dendritic cell?
Messengers
Eat a small amount of pathogen to see if it’s healthy or infected
Migrate to lymph nodes - instruct T cells
What is dendritic cell differentiated by?
Factor Flt3L
What are monocytes differentiated by?
M-CSF
What do dendritic cells and monocytes have?
Different transcription factors
Where is location of dendritic cell?
Body surfaces
Organs
T cell areas of lymphoid organs
What are the sensors of dendritic cells?
Antigen uptake
Processing and presentation of peptide-MHC complexes
What is maturation of dendritic cells?
Response to microbial and other stimuli
What are the subsets of dendritic cells?
With distinct pattern recognition receptors and function
e.g. pDCs, CD8+ and DC
Where are majority of DC found?
Aortic Arch where the blood slows down
In the lymph node, where are macrophages found?
Marginal zone around the outside
Clumps of B cells
T cells are on the inside with dendritic cell
What does dendritic cell have an array of?
DAMP and PAMP to sense the environment
What are PAMP known to be?
Very stimulatory
What are different methods of uptake?
Specific
Non specific
Specific
Receptor in the membrane e.g. Clathrin(receptors for sugars)
Uptake is common for uptake of bacteria
Phagocytosis
Non specific
Engulf soluble antigens
What are endogenous pathogen?
Virus
Pathogen will be presented with a MHC I molecule
Activate CD8 T response
What are exogenous pathogen?
Bacteria
Phagocytosed and processed and presented with a MHC class II molecule
Activate CD4 T response
Where is MHC I assembeld?
In ER with antigen coming from cytoplasm
What is an example of MHC I assembly?
Virus
Protein degraded in proteosome
Where is MHC II assembled?
ER
2 alpha and 2 Beta chains stabilised by invariant chain
Travels through Golgi to late endosomes
Lysosome in presence of low PH = degraded
Frees space for the peptide to bind MHC II
Antigen binds and then go to membrane
Where is MHC I loaded?
ER
Where is MHC II loaded?
Endocytic compartment
What can dendritic cell initiate?
Adaptive immune response
When does MHC class I only occur?
If the cell is infected
How do you present an MHC class II response when not infected?
Cross-presentation
Cross-presentation of exogenous antigens on MHC I
Antigen phagocytosed Enters endosomes which become leaky Antigen leaks to cytoplasm Goes to proteosome where it is degraded Loaded in the ER onto MHC I complex and presented in membrane
Semi-immature DC
Have some activation but not enough to produce a cell response
Doesn’t respond to dangerous pathogens
Mature DC
Induce immunity
Tell T cells what to do/activate them
Super activated DC
When the stimulus is too strong
What does surrounding environment of DC determine?
Which type of T cell response will be induced via cytokines production
What does DC maturation drive?
MHC-peptide complex formation
What are MHC class II restricted to?
Macrophages
B cells
DC
Why is macrophage/immature DC not a good APC?
Once the antigen is taken up, it binds to lysosome which has a very low PH
Degrades the protein = destroyed
Mature DC
In a steady state
High basic PH in lysosome which block degradation of antigen
What is the lysosomal PH of immature DC?
5.5
What is the lysosomal PH of mature DC?
4.5
What is the PH optimal for lysosomal proteases?
< pH 5
When MHC II reaches the lysosome and there’s a drop in PH, what does it induce?
Activation of catS and catL
This degrades Li chain
What does HLR-DM remove?
CLIP
Allows peptide to bind to MHC II
Goes to membrane
What can mature DC prevent?
Induction of autoimmunity
Why does MHC II go to the membrane?
Degraded, recycled and synthesised continuously in a cycle
What does MHC II have a signal for?
Proteosome degradation called MARCH 1
Why does MHC II remain in the membrane for much longer?
facilitates interaction with T cells
What does maturation cause?
Rapid migration of splenic and LN DC to T cell area
Promotes upregulation of costinulation and cytokine production
Increase antigen presentation
Reduce phagocytosis
What are main features of DC maturation?
Enhance antigen processing
Migration to lymph node
Production of cytokines/ chemokines
Up-regulation of co-stimulatory molecules
What is the cell that induce cross-presentation?
cDC1
What do CdC2 tend to be?
Better CD4 inducers
What is CD103?
Very immunosuppressive in gut
Induce regulatory T cell recruitment
What is Dendritic cells often a target for?
Vaccination
Only cells that produce adaptive immune r spines
What are dendritic cell being manipulated for?
Immunotherapy
