Immunology (Liz lectures 2-4 - Antigen presentation) Flashcards
Do T lymphocytes bind to to soluble antigens in the blood or to antigenic fragments presented on MHC molecules?
Only bind to antigens presented on MHC
Why is it important that cytotoxic T cells only respond to MHC presented antigens?
Production of cytotoxic reagents by cytotoxic T cells to soluble viral particles could be dangerous to normal cells
Why is it important that helper T cells only respond to MHC presented antigens?
- If T helper cells reacted to soluble antigens it could cause uncontrolled cytokine production which can lead to autoimmunity
What is the structure of the proteasome?
- Large cylindrical complex
- 28 subunits arrange in 4 stacked rings of 7 subunits each
- PA 28 binds to both ends of proteasome and is called proteasome activator
- PA 28 changes the conformation of the alpha subunit allowing protein entry
What signals cause the production of PA28?
Only produced in response to IFN-gamma or TNF-alpha during inflammation
- replaces normal 19S cap
In response to these cytokines, the 3 enzymes beta1, beta2 and beta5 are replaced by what 3 different enzymes?
beta1i, beta2i and beta5i
What is the name for the proteasome after these changes have occured in response to inflammation?
The immunoproteasome
What tag is added to the viral proteins to target then to the immunoproteasome?
Ubiquitination
- polyubiquitin chain added
- Protein degraded into small antigenic fragments that bind better to MHC class I
How does the immunoproteasome sometimes contribute to autoimmunity?
- Increased processing of self proteins through cell with high immunoproteasome levels
- Increased self antigens expressed on MHC class I
What are the functions of the TAP1 and TAP2 transporters on the ER membrane?
Transport peptides from the cytosol into the ER lumen
What type of transporters are TAP1 and TAP2?
Part of the ATP-binding cassette (ABC) family
What happens in people have defects in TAP1 and TAP2?
- Almost no MHC class I on cells
- Recurrent respiratory viral infections
Describe how MHC class I is assembled
- Imcomplete MHC class I consists of 3 alpha subunits: 1,2 and 3
- Imcomplete MHC class I bound to protein chaperone called calnexin
- The beta-2 microglobulin binds to complex to complete MHC - calnexin dissociates
- MHC then binds to chaperone proteins calreticulin and ERp57
- These proteins cover antigen binding site of MHC
- Binding of complex to TAP via tapasin
- Calreticulin and ERp57 dissociate, allowing binding of degraded cytosolic proteins and defective ribosomal products (DRiPs)
- MHC class I will antigen bound is transported to the cell membrane in an endosome
What are DRiPs?
Defective ribosomal products
- include unstable proteins translated from mRNA
- can be both self and pathogen derived
- Recognised and tagged by ubiquitin for degradation by proteasome
What is ERAAP?
Endoplasmic reticulum aminopeptidase associated with antigen processing
- trim amino-terminus of peptides if they are too long
- Helps to fit peptides into MHC class I groove
ERAAP is regulated in response to what cytoking?
Interferon gamma (IFN-gamma)
Give some examples of how viral immunoevasins interfere with MHC processing
1) US6 and ICP47 prevent peptide movement through TAP
2) Adenovirus protein E19 competes with tapasin - inhibits peptide loading onto MHC
3) mk3 protein of mouse herpes virus - is a E3-ubiquitin ligase - ubiquitinates cytoplasmic tail of MHC I - targets it to the proteasome
Describe in basic the endosomic (class II) pathway of antigen processing
- Antigen ingested by endocytosis or phagocytosis
- Endosome fuses with lysosome
- Antigens degraded and intergrated into MHC class II
- MHC class II-peptide complex presented on cell membrane
What cells perfom class II antigen processing and how long does it take?
Only APCs e.g. macrophages, B cells and dendritic cells
Takes 1-3 hours
What does each class on TLR bind to?
1,2,4,5 and 6: bind to components on the surface of pathogens e.g LPS on bacteria
3,7,8 and 9: bind to rna or dna