Antigen Presentation Flashcards
What do T cell receptors (TCRs) recognize on antigen-presenting cells? What is it known by?
The peptide AND the MHC receptor
MHC-restriction
What is the process of ‘central tolerance’?
developing T cells (thymus) and B cells (bone marrow) are tested for self-reactivity
Those that strongly recognise self-antigens are eliminated or inactivated to prevent autoimmunity
Why did the adaptive immune system evolve to recognise peptides attached to MHC?
Need to detect pathogens which are intracellular (e.g. viruses) as they are not directly visible to the immune system
MHC offers a way to display internal antigens at the cell surface
What are the primary methods of antigen uptake by APCs?
Macrophages - Phagocytosis
Dendritic cells - Viral infection
B cells - Antigen-specific receptor
What types of cells can present peptides on MHC-I?
All nucleated cells
What types of cells function as professional APCs, and how are they distinguished?
Dendritic cells, macrophages and B-cells
Able to present MHC-I and -II
Able to deliver co-stimulatory signals
Able to activate naïve T-cells
How are cytosolic antigens processed for presentation via MHC-I?
Degraded in the cytosol
Intracellular pathogens (e.g. viruses) can infect any cell
Proteins present inside the cytosol (self or viral) get broken down into peptide fragments by the proteasome
TAP delivers peptides to the ER
Peptide binds the MHC-I molecule and completes its folding
The MHC-I molecule is released from the TAP complex and exported to the cell membrane
How did the immunoproteasome develop and what is its action?
Starts as a normal proteosome
Once cell becomes infected it becomes activated and starts producing type 1 interferons
This turns on genes which protect the cell from infection
Some genes are additional subunits that get tacked on to original proteosome
Turns into immunoproteasome
Becomes more specialised in producing peptides that are likely to fit in peptide binding groove of MHC-I
What is the action of ERAAP?
Once peptides -> ER more enzymes edit peptide to size likely to bind to MHC-I
Trims larger peptides to enable a good fit in the MHC-I groove
What steps are involved in processing extracellular antigens for presentation via MHC-II?
Invariant chain (Ii) forms a complex with MHC class II molecule, blocking the binding of peptides and misfolded proteins
Ii is cleaved in an acidified endosome, leaving a short peptide fragment - CLIP
○ Still bound to MHC class II molecule
Endocytosed antigens are degraded to peptides in endosomes, but the CLIP peptide blocks the binding of peptides to MHC-II molecules
HLA-DM binds to MHC-II and releases CLIP, allowing other peptides to bind
MHC-II travels to the cell surface
What is cross-presentation, and how does it bypass conventional antigen processing rules?
It allows antigens acquired from vesicles to be presented on MHC-I
Why is cross-presentation important?
Dendritic cells at the infected site can sample the local environment by macropinocytosis but need to present on MHC-I
Specialist dendritic cells can pick up viral antigens from the dead dendritic cells via an endocytic route (vesicles)
What role do MHC molecules play in presenting antigens to T-cells?
MHC must be able to bind to a wide range of T-cells: high affinity
Binding has to be stable, if unstable:
○ Pathogen detection lost
○ MHC on uninfected cell could pick up peptide released by infected cells and wrong cell would be killed/activated
Single aa change in peptide can alter responsiveness of TCR
What are the differences between MHC-I and MHC-II structure?
MHC-I = single a-chain + b2-microglobulin
○ Anchor residues at fixed points from ends
○ Different motifs have been defined for different HLA types
MHC-II = a and b chains
○ No anchor residues, there is anchorage along the length of groove
What is the significance of MHC polymorphism and polygenicity for immune diversity?
Need to be able to present any antigen that poses a threat
○ Different combinations of a and b chains
Polymorphism leads to diversity in the peptide binding pocket
What is the meaning of polygenic and polymorphic?
Polygenic = multiple genes per individual
Polymorphic = many different alleles within the population
What 3 signals do APCs deliver to naïve T-cells to induce full activation and why?
TCRs only recognise complexes of MHC and peptide
Co-stimulatory molecules such as B7.1 and B7.2, upregulated on APC
○ Tells T-cell that the peptide present is a pathogenic infectious foreign agent
Secrete cytokines which will define which type of T-cell they produce
○ Shapes immune response
Why is it important for antigen processing and presentation to occur in distinct cellular compartments?
At site of infection
○ Antigen uptake by dendritic cell
○ Antigen processing
Lymphnode
○ Antigen presentation to lots of TCRs
○ T-cell proliferation
Systemic circulation -> site of infection
○ T-cell goes back to infection site and looks for epithelial cells presenting viral peptide on MHC-I
Why is the immune system selecting self reactive T-cells?
Immature T-cells whose TCRs interact strongly with ‘self’ peptide:MHC’ need to be dealt with as they are more likely to lead to immune reponses
What mechanisms prevent self-reactive T-cells from causing autoimmunity (central tolerance)?
Central tolerance = process of getting rid of T-cells
Reduce the chance of an autoimmune response
T-cells can undergo gene arrangement to remove self-reactivity or face functional inactivation (anergy) or even deletion by apoptosis
Can be pushed towards a regulatory (suppressive) T-cell phenotype
