Describe processing & presentation of exogenous Ag and explain the consequences.
- Ag degraded by proteasome
- Resulting peptides are translocated via transporter associated with Ag presentation (TAP) into ER lumen and loaded onto MHC class I molecules
- Peptide-MHC class I complexes are released from the ER and transported via the Golgi to the plasma membrane for Ag presentation to CD8 T cells
What is the purpose of antigen presentation?
- Educate the immune system and the discrimination of self versus non-self (foreign) Ag
- Through Ag presentation, cells display their proteome on their cell surface providing information of a cell’s health
- THUS - Ag presentation is essential for not only pathogen-specific immune response but also immune tolerance
What is an antigen?
Any substance that can be recognized by the antigen receptor of a B cell or by the T cell receptor when complex with MHC molecules
How do B cells see Ag?
Directly via BCR (slg)
B cells detect native (unprocessed) Ag
How do T cells see Ag?
T cells interact with Ag complexed with MHC (Major histocompatability complex)
How do T cell receptor interact with peptide-MHC molecule?
- T cell receptor interacts with peptide and the presenting MHC molecule
- Different MHC molecules present different peptides based on the peptides that fit and stable within MHC groove
- Strength of interaction determines type of response
What is the difference in length of MHC class I and class II?
Class I - 8-10 aa
Class 2 - 15-24 aa
What are the roles of Ag presentation in health and disease? Which roles if awry, cause autoimmunity?
- Transplantation
- Central tolerance - dvlping T cells
- Peripheral tolerance - mature T cells
- Pathogen immunity
- Tumour immunity
Central tolerance and peripheral tolerance
What are the three ways an immature T cell can develop into?
- Death by neglect
- +ve selection of conventional T cells
- -ve selection of autoreactive T cells
What recognizes MHC class I?
CD8 cytotoxic T cells
What recognizes MHC class II?
CD4 helper T cells
Compare professional and non-professional APCs.
Non-professional APCs include all nucleated cell types in the body
Professional APCs = DCs, Macrophages, B cells
- Present Ag with MHC class I and MHC II molecules
- DCs are especially equipped to activate naive T cells
What are the two ways extracellular Ag can be uptaken for the presentation by MHC class II molecules?
- Ag uptake via B cell receptor
- Ag uptake by PRRs, C type lectin receptors, Fc receptors, scavenger receptors, constant sampling
Describe processing & presentation of MHC class II and explain the consequences
- MHC class II a- and b-chains assemble in the ER and form a complex with the invariant chain (Ii).
- Ii-MHC class II heterotrimer is transported through the Golgi to the MHC class II compartment (MIIC).
- Endocytosed proteins and Ii are degraded by resident proteases in the MIIC
- The class II-associated Ii peptide (CLIP) fragment of Ii remains in the peptide-binding groove of the MHC class II dimer and is exchanged for an antigenic peptide with the help of the dedicated chaperone HLA-DM
- MHC Class II molecules are then transported to the plasma membrane for recognition by CD4 T cells
What is cross-presentation/cross-priming essential for?
- Allows CD8 T cells to see exogenous Ag
- Cross-priming enables extracellular Ag to be presented to CD8 T cells - Critical for immunity against most tumours & some viruses
Compare the 3 types of professional APCs.
Dendritic cell:
Ag uptake & recognition - constant sampling PRRs
Costimulatory activity - +++
T-cell activation - naive, effector and memory T cells
Importance - crucial to launch T cell adaptive response
Macrophage:
Ag uptake & recognition - non-specific PRRs
Costimulatory activity - ++
T-cell activation - effector & memory
Importance - re-stimulates effector Th in tissues
B cell:
Ag uptake & recognition -
Costimulatory activity
T-cell activation
Importance
When does antigen stimulation under non-inflammatory conditions happen?
- Lack of co-stimulatory molecules
- Lack of inflammatory cytokines
TOLERANCE
What happens during antigen stimulation under inflammatory conditions?
- Increased co-stimulatory molecule expression
- Increased inflammatory cytokine production
IMMUNITY
What happens to T cells when they get activated?
Naive T cell (day 0) ➔ effector T cell (day 8) ➔ memory t cell (>day 40) or apoptosis
Where are naive T cells found?
Lymph, blood
Where are effector and memory T cells found?
lymph, blood and tissues
What is the lifespan of the different types of T cells? (From shortest to longest)
effector < naive < memory
How do B cells differentiate?
B cell ➔ effector cell ➔ plasma cell
