Lecture 15 - APCs II Flashcards
What is important about the generic sort of signals that stimulate DCs?
Danger signals: exogenous AND endogenous
Not solely pathogens signals
What happens when mitochondria become damaged?
Cell automatically undergoes apoptosis
Mitochondrial DNA that leaks out binds PRRs in the cytosol
Describe the sequence of events that occur when the DC experiences LPS
- LPS binds TLR 4 on DC surface
- Induction of a signal transduction pathway involving MyD88
- NFKB activated
- NFKB translocated to nucleus and turns on gene expression
- IL-6 production
Where are the different locations of TLRs?
Cell surface
In endosomes
i.e. must be associated with a plasma membrane
Describe how DCs recognise viruses and bacteria
Viruses: the DNA / RNA stimulates PRRs
Bacteria: flagella, LPS etc stimulates PRRs
Which PRR recognises LPS?
TLR 4
Describe the adherence of DCs in tissues before maturation
DCs (e.g. Langerhans cells) present in epidermis; weaved into the keratinocyte network
Adherence through various molecules:
• E-cadherin
- experience of antigen -
Down regulation of E-cadherin
Upregulation of CCR7
Describe migration of DCs to the lymphoid organs
DCs become unstuck
Lymphoid organs release chemokines, creating a gradient
• CCL19
• CCL21
Chemokines specifically
DCs follow a gradient towards the lymphoid organs
• CCR7
• receptor on DCs that allow them to recognise the chemokines being released by lymphoid organs
Where are T cells found in lymph nodes?
Paracortex
Through which structure do DCs get into the lymph nodes?
What else comes through in this way?
Afferent lymphatics
Whereas naïve T cells come in via HEV
Where do DCs specifically go in the lymph node?
Paracortex: i.e. where the T cells are
Describe cross presentation
Compare with direct presentation
MHC I presenting peptide from an exogenous source
- Extracellular antigen translocated into the cytosol, where it is loaded onto MHC class I
- We now have exogenous peptide on MHC I for presentation to CD8+ T cells
In direct presentation cytosolic peptide binds to MHC I while it is still in the ER
NB This is thought to be an artificial system
Why is cross presentation so important?
DCs can present viral peptides on MHC I without being infected
Can present peptides from viruses that circumvent DCs
What happens if a pathogen does not infect DCs?
Potentially, the antigen won’t be presented to T cells
Describe antigen presentation for HSV
• HSV only infect the epidermis
• DCs sit next to the infected keratinocytes
• DCs present viral peptide on MHC I
etc.
Which path of antigen presentation is best for extracellular bacteria?
Why?
MHC Class II
Primes CD4+ T cells:
• ‘helper’ T cells release cytokines to kill the bacterium
• help for B cells to produce Ab
Which path of antigen presentation is possible for soluble antigens or virus particles?
MHC Class II
and
MHC Class I (via cross presentation)
How are soluble antigens & virus particles taken up by APCs?
Macro-pinocytosis
How are extracellular bacteria taken up by APCs?
Receptor mediated phagocytosis
Which path of antigen presentation is best for viruses?
MHC class I pathway
Which path of antigen presentation is best for extracellular viruses particles?
MHC II
What are the different mechanisms for viral antigen presentation on MHC I?
- Cell is infected
• Protein being made in the cell - Cross presentation
• Phagocytic / macropinocytic uptake of virus
• Degraded
• Presented in MHC I - Transfer from incoming DC to resident DC (in LN)
Describe antigen presentation of intravesicular pathogens
- In intracellular vesicle
- Degraded in vesicle
- Loaded into MHC II (in MIIC)
- Presented to CD4+ T cells
Describe the three signals required for antigen presentation
Signal 1: TCR-MHC interaction
Signal 2: Co-stimulation
• CD80, CD86 and CD28
Signal 3: Release of soluble factors from DC (e.g. cytokines)
How does a naïve T cell receive co-stimulation?
CD28 already present on its surface
Why is co-stimulation sometimes not required for T cell stimulation?
- Second viral infection (e.g. HSV)
- Memory CD8+ T cells
- CTLs stimulated by non-professional APCs which are presenting the viral peptide in the context of MHC I
- These non-professional APCs are not expressing co-stimulation molecules
• However, these CTLs don’t need co-stimulation for proliferation
What process will only occur after signal 2?
Proliferation of the T cell after antigen presentation from APCs
Without co-stimulation, proliferation will not occur
Why is Signal 3 important?
Informs the ‘Functional Polarisation’ of the activated T cell
(i.e. guides the differentiation into all the different Th cells)
Give some examples of Signal 3 informing functional polarisation
IL-4 released in Signal 3 → Th2
IL-12 → Th1
IL-6 → Th17 (extracellular pathogen, neutrophil induction)
Why are adjuvants added to vaccines?
Adjuvants drive signal 2 & 3
Thus they are vital for a robust immune response when using a killed / inactivated vaccine
Describe the role of CD40 in antigen presentation
APCs up-regulate CD40 after experiencing the antigen
CD40 interacts with CD40L on the naïve Th cell during activation
Why is cross presentation so immunologically important?
Potential for some viruses never to be presented in the context of MHC class I:
• Kill DCs upon infection
• Don’t infect DCs
Cross presentation allows DCs to present these viral antigens in the context of MHC I
Describe the importance of cross presentation in tumour immunity
- CTL response important for tumour cells
- DCs need to present the tumour cells antigens in the context of MHC class I
Mechanism:
1. Many tumour cells dying at any point in time:
• In malignant tumours angiogenesis is not sufficient for new cell growth and there are thus many tumour cells dying
• immune mediated killing of tumour cells
- Once the cells die, DCs take up the antigen
- Cross presentation of the antigen occurs, Ag presented in the context of MHC class I
- Induction of CTL response
