Part 1: Antigen processing Flashcards
What can CD4 & CD8 increase the sensitivity of ?
CD4 & CD8 can increase the sensitivity of T cells to peptide-antigen MHC complexes by ~100 fold
What 3 signals are required for activation of T cells by APC?
- Antigen-specific signal: peptide&MHC binding the TCR & coreceptor
- Costimulatory signal: T cell costimulatory CD28 binds B7 on APC
- Cytokines: IL-2 (key growth factor) & other differentiation cytokines and transcription factors
Explain Signal 2: Co-stimulation via CD28 & B7 molecules ?
- CD28
- Found on T cells and needed for T cell autocrine secretion of IL-2
- Constitutively expressed on T cell surface. Upregulated after
activation - CTLA4
- Found on T cells and upregulated after T cells are activated.
- Competes with CD8 for B7 to switch T cells off at the end of an immune response - B7
- Has two forms: B7.1 (CD80) and B7.2 (CD86)
- Functional difference between B7.1 and B7.2 not known
- Found on activated antigen
presenting cells
What happens if there is no costimulation ?
T cells can neither divide ot survive
What does Co-stimulation provide ?
Co-stimulation provides an simultaneous signal to
permitting activation
Co-stimulation is restricted. What does this mean ?
Only Dendritic cells, macrophages & B cells express co-stimulatory molecules in the presence of infection/danger
Function of Phagolysosomes?
- Vesicles fuse with lysosymes
- Acidification of vesicle activates proteasomes & hydrolases to degrade the contents into peptides
Where are MHC class II generated ?
In the ER
What does the Invariant chain?
Prevent peptides from binding MHC until it reaches the site of extracellular protein breakdown
What does HLA-DM catalyse?
Release of CLIP fragment of invariant chain
Invariant chain is cleaved to form ?
CLIP (class II associated invariant peptide) in endosomal compartment
The invariant chain is identical in all individuals and functions:?
- Prevent peptide binding
- Stabilise the conformation of the MHC class II (MIIC) until it binds peptide
- Deliver MHC class II into specialised endocytic vesicles where they bind peptides
What does MIIC proteases do?
Selectively attack Ii leaving CLIP on peptide binding grove
Peptide loading complex:
Chaperone proteins involved in the formation of the MHC I heterodimer
(1) Calreticulin & ERp57 stablisise until β2-microglobulin binds
(2) Tapasin facilitates binding to TAP which delivers peptides to MHC class I
Peptide loading complex aids the assembly & peptide loading of MHC I in ER
- Degredation of proteins by the proteasome (cytosol) produces peptides
- TAP delivers peptides to the ER
- MHC class I is retained in the ER until peptide binds, completing the folding
- The complex is then release from the ER for delivery to the membrane
Explain CD8+ ‘cytotoxic’ T cells (CTLs) ?
- Generated in the thymus
- Express T cell receptor & dimeric CD8 co-receptor
- Recognise peptides presented by MHC Class I molecules (on all nucleated cells)
- Important for immune defence against intracellular pathogens (viruses & bacteria) & tumour surveillance
CD4+ versus CD8+ T cell Function ?
CD8+ T cell
- Antigen specific killing of target (self) cell
- Recognise antigen on MHC class I
- Receive signals for activation
(a) with CD4+ T cell help
(b) without CD4+ T cell help - Produce cytokines
- 2 major killing mechanisms:
(a) Cytotoxic granule release
(b) Fas-Fas-L killing
CD4+ T cell
- Differentiate into helper cell subsets
Activation of killing by CTLs is highly destructive, requiring three signals:
- Priming by activated antigen presenting cells expressing
antigen on MHC I - Dendritic cells must have high intrinsic co-stimulation
- CD8+ T cell can then make its own IL-2 to drive proliferation
Some CD8+ cytotoxic T cell responses require ?
CD4+ T cell help
The problem -
Naive antigen-specific CD8+ T cells cannot directly eliminate transformed or infected cells without first to be activated by ‘professional’ APCs
What if the APC is not directly infected?
The solution -
- APCs need to acquire exogenous antigens from
the infectious agent and present them on MHC class I molecules - known as cross-presentation.
- Cross-presentation allows APCs to acquire antigens from non-APCs e.g. virally infected epithelial cells and present them on both MHC class I & MHC class II
- This provides the best stimulation for CTL activation
What are Natural Killer T cells?
Lymphocytes with innate immune function - a first line of defence
What are Natural Killer T cells important against ?
Particularly important against viral & bacterial infections and detection/limit development of cancer
Death of target cells ?
Protective outcomes of CTLs and NK cells use different targeting mechanisms, but induce the same outcome
NK cell receptors – licensed to kill by ?
‘Dysregulated self’
