Antigen Presentation
- what is it and why do we do it?
- An immuno-surveillance system for the detection of intracellular pathogens (ie. viruses and intracellular bacteria) and abberant cell changes (ie. pre-cancerous cells).
- Function: To enable the rapid detection of invading pathogens and allow the orchestration of specific cellular immune responses capable of eliminating pathogens and infected cells.
- By capturing fragments of degraded proteins, antigen-presenting molecules display, or ‘present’, on the cell surface an up-to-the-minute, molecular snapshot of what is happening inside individual cells.
T lymphocytes are constantly circulating and scanning the repertoire of antigens presented at the surface of cells, and can recognize subtle changes that may be indicate infection or tumorigenesis
What are critical distinctions within each of the concepts?
- antigen presentation
- antigen processing
- antigen-presenting cells
- immune evasion
•Antigen presentation:
Ø MHC class I vs. MHC class II
(CD8+ T cells) (CD4+ T cells)
Ø Direct presentation vs. cross-presentation
•Antigen processing:
Ø Endogenous vs. exogenous antigens
•Antigen-presenting cells:
Ø Professional vs. non-professional
•Immune evasion:
Ø Viruses vs. tumors
Major players with antigen presentation?
Which cells present antigens? (think about profession vs non-professional APCs)
Discuss the different sources of antigens
MHC Class I vs II
- peptide-binding groove
- chains
- endocytic motifs
Optimal peptide sizes for MHC class I vs II?
What are the genes encoding for MHC?
HLA
Where are the polymorphic hot spots for MHC?
Why are HLA molecules so polymorphic?
- MHC polymorphism among individuals is thought to provide a survival advantage to the species as a whole.
- By having thousands of HLA alleles, an emerging pathogen (ie. viruses) will be less likely to render the entire species extinct.
- Some subset of individuals expressing ‘advantageous’ HLA alleles will be capable of generating effective immunity against the pathogen and thus will survive a potential outbreak.
How is protein translation intimately coupled to endogenous antigen presentation by MHC-I?
- Newly synthesized proteins are the major source of peptides presented by MHC-I molecules.
- Most peptides are derived from defective ribosomal products (DRiPs), proteins that are damaged or misfolded and rapidly degraded.
(DRiP t1/2 = minutes)
- Surprisingly, healthy and properly-folded proteins with (t1/2 = hours or days) are eventually degraded, but are not a source of peptides for presentation at the cell surface.
- Allows for extremely rapid presentation of viral peptides during infections.
(Time is of the essence during pathogen invasion)
Describe the proteosome
- structure
- location
- functional activity
- A large multi-subunit protein complex
- Resides within the cytosol
- Has proteolytic activity
- Cleaves newly-synthesized proteins into short peptides
- Functions in:
- antigen presentation
- turnover of signaling molecules
- turnover of cell cycle proteins
- apoptosis
What is the Classical MHC class I ‘direct’ antigen presentation pathway?
MHC Class I Direct Presentation Pathway: Describe it
What is Transporter Associated with Antigen Processing (TAP)?
How do viruses perform Immune evasion by subverting MHC class I antigen presentation?
How do tumors perform Immune evasion by subverting MHC class I antigen presentation?
How does antigen presentation influence T-cell development?
What are general features of exogenous Ag presentation by professional APCs?
Diagram of classical Antigen presenting pathways
What is the invariant chain and how does it become “CLIP?”
What is the role of the invariant chain in MHC Class II Ag presentation?
What is cross-presentation and what’s the significance of it?
some pathogens may infect somatic cells but not directly infect phagocytes such as DCs. Dcs must acquire antigens from exogenous sources in order to process and present antigens to T-cells e.g. to eliminate a virus that infects only epithelial cells, activation of CD8+ Tcells will require that DCs load MHC class I molecules. The exogenous pathway of loading MHC I molecules is called cross-presentation.
Not fully understood mechanism but in DCs, MHC class I molecules traffic from the cell surface into LAMP-1+ endosomal peptide-loading compartments (ELCs) by way of a
highly conserved, tyrosine-based endocytic motif.
What is conserved in MHC-I cytoplasmic tail sequence between humans and mice?
H-2Kb cytoplasmic tyrosine is required for its _____________.
serine and tyrosine residues.
H-2Kb cytoplasmic tyrosine is required for its endolysosomal trafficking and exogenous antigen acquisition [important in cross-presentation]
