L6 - Adaptive immunity 3 Flashcards
What happens during activation of T-cells
- Antigen presenting cells (APCs) determine which peptides will be presented on class I and class II MHC during initial activation
- T-cells need to be able to distinguish between external antigens (taken up by APCs) and internal antigens (infected cell)
What is antigen processing?
- Enzymatic process of degrading proteins through proteases into antigenic peptides
- Antigen processing requires energy (ATP) and movement of endocytic vesicles
Process of MHC class II presentation
- Extracellular antigen enters cell via endocytosis and an endocytic vesicle forms
- Peptide production in phagolysosome
- Peptide binding by MHC class II
- MHC class II presents peptide at cell surface
Process of MHC class I presentation
- Intracellular antigen enters proteasome (antigen processing to peptides in proteasome)
- Peptide transport into endoplasmic reticulum
- Peptide binding by MHC class I
- MHC class I presents peptide at cell surface
Specific immune cells for each antigen processing pathway
- Endogenous antigens in cytosol presented on class I MHC molecules to CD8 T cells and tumour cells
- Exogenous antigens in endosomes presented on class II MHC molecules to CD4 T cells
Action of the proteasome
- Unfolds proteins and then cleaves proteins into peptides and amino acids
How are peptides produced in the cytosol transported into the endoplasmic reticulum after proteasome processing
- Via the TAP transporter
Features of TAP proteins
- TAP (transporters associated with antigen processing)
- TAP 1 and TAP 2 form heterodimer in membrane of ER to facilitate selective transport of peptides from cytoplasm into lumen of ER
- TAP pump preferentially transport peptides with a length of 8-15 amino acids
Process of MHC class I molecule
- Class I heavy chain is stabilised by calnexin until B2-microglobulin binds
- Calnexin is released. The deterodimer of class I heavy chain and B2m forms the peptide-loading complex with calreticulin, tapasin, TAP and ERp57
- A peptide delivered by TAP binds to the class I heavy chain, forming the mature MHC class I molecule
- The class I molecule dissociates form the peptide-loading complex, and is exported from the endoplasmic reticulum
Activation of CD8+ Tc by endogenous or intracellular antigens
- Effector CD8+ Tc (CTLs) are primarily needed for the eradication of infected cells
- CTLs can also be activated against cancer cells (tumour) targets ‘neo antigens’
CTL killing of infected target cells
- Viruses must replicate inside cells and many bacteria and parasites live inside host cells
- Therefore antigens for stimulating CTLs come from inside the cell because they signal an intracellular infection
Immune evasion - viruses can interfere with Class I MHC expression to escape killing by CTLs
- Herpes simplex virus (HSV) protein ICP47 can selectively bind to TAP and inhibit the transfer of peptides into ER
How are peptides generated in the endocytic processing pathway
- Antigen is taken up into intracellular vesicles
- In early endosomes of neutral pH endosomal proteases are inactive
- Acidification of vesicles activates proteases to degrade anigen into peptide fragments
- Vesicles containing peptides fuse with vesicles containing MHC class II molecules
Where are peptides bound to MHC class II molecules derived from
- Derived from engulfed pathogens (and internalised TM proteins)
- Acidification of endocytic vesicles activates proteases that degrade proteins into fragments
- These peptide fragments are loaded onto MHC class II molecules
Trafficking of MHC class II molecules
- MHC class II alpha and beta chains associate in the ER
- In the trans golgi network, MHC class II is sorted into vesicles
- These vesicles deliver MHC class II to specialised compartments where peptide loading occurs
What prevents MHC class II from binding ‘self’ peptides in the ER
- Invariant chain blocks binding of peptides to MHC class II molecules in the ER
- In vesicles, invariant chain is cleaved, leaving the CLIP fragment bound
- CLIP blocks binding of peptides to MHC class II in vesicles
- HLA-DM facilitates release of CLIP, allowing peptides to bind
Function of HLA-DM
- HLA-DM acts like a chaperone for MHC class iI molecules and catalyses the release of CLIP once an antigenic peptide is present
Exogenous pathway - Class II MHC peptide loading
- Class II MHC loading takes place in endosomes where acidic pH is required for protein degradation into peptides
- Invariant chain is degraded and CLIP is exchanged with foreign peptide
CD4+ Th activation by exogenous antigens
- Foreign antigens/extracellular pathogens need to be taken up by APCs to get noticed by Th cells of the immune system
- This leads to activation of macrophage and the production of secreted antibody by plasma cells
Viral inhibition of Class II MHC
- Adenovirus interferes with class II upregulation in APCs
- The HSV viral envelope protein, glycoprotein B, reduces MHC class II processing and inhibits the production of invariant chain peptide
- HIV interferes with Class II processing
Pathogens that evade lysosomes
- Leishmania and mycobacteria (TB) prevent phagosome-lysosome fusion
How are T-cell antigens kept apart?
- Class I and class II MHC molecules both traverse through ER to cell surface but load peptides in different cell compartments
- Control is through accessory proteins
Accessory proteins that control T-cell antigens
- Class I requires TAP, tapasin, etc control
- Class II requires low pH for removal of li
Summary of T-cell dependent B-cell response
- Antigen binding to BCR provides ‘signal 1’ to B cell
- Antigen is internalised, processed and antigenic peptides are displayed on MHC for T cell recognition
- Th (helper T cell) recognises antigen-MHC complex via the T cell antigen receptor(TCR): provides ‘signal 1’ to T-cell
- CD80 on B-cell binding to CD28 on T-cell provides ‘signal 2’ to T cell
- T-cell activation leads to up-regulation of CD40L which bind to CD40 providing signal 2 to B cell
- Cytokine production by activated T cell also help to activate B-cell
- B-cell proliferates and differentiates into antibody secreting B-cell (plasma cell)