6. Adaptive immunity 3 Flashcards
MHC and their antigens
MHC class I presents peptides from endogenous proteins
MHC class II presents exogenous or membrane-derived peptides
T cells and MHC
CD8+ T-cells recognise MHC class I CD4+ T-cells recognise MHC class II
Why do T cells need antigen presentation?
Unlike B cells, T cells cannot recognise native antigen
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
MHC class II pathway
Extracellular antigen internalised in endocytic vesicle, processed into peptides in phagolysosome
MHC class II enters lysosome
peptides bind MHC class II molecule
phagolysosome fuses with cell membrane and MHC class II presents peptide at cell surface
MHC class I pathway
intracellular antigen (e.g. from cancer cell or virally infected cell) processed in proteasome into peptides
Peptide transported into ER
MHC class I binds antigen at ER membrane
MHC class I presents peptide at cell surface
Two antigen processing pathways
Endogenous antigens in cytosol presented on class I MHC molecules to CD8+ T cells
Exogenous antigens in endosomes presented on Class II MHC molecules to CD4+ T cells
Neoantigens produced by cancer cells, not recognized as self so are recognized by immune system
Endogenous antigens
Endogenous antigens are from proteins produced inside the cell
These includes self protein antigens and foreign protein antigens
Class I MHC antigens activate cytotoxic CD8 T-cells for killing infected cells and tumour cells
Endogenous antigens proteasome
Immunproteasome is a bit different to constitutive proteasome, has PA28 caps instead of 19s caps
The proteasome unfolds proteins and then cleaves proteins into peptides and amino acids
Where do peptides produced in cytosol go?
peptides produced in the cytosol are transported into the endoplasmic reticulum via TAP protein
TAP proteins
TAP proteins (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
Calnexin’s role in antigen processing
Class I heavy chain is stabilised by calnexin, but this becomes displaced when B2-microglobulin binds
Calnexin is reelased and heterodimer of class I heavy chain and B2m forms peptide loading complex with calreticulin, tapasin, TAP and ERp57
Peptide delivered by TAP binds to class I heavy chain to form mature MHC class I molecule
Class I molecule dissociates from peptide-loading complex and is exported from the ER
What activates CD8+ T cells?
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
Viral 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?
- Peptides bound to MHC Class II molecules are 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 stops MHC class II binding self peptides?
CLIP (Class II associated Invariant chain Peptide)
HLA-DM acts like a chaperone for MHC class II molecules and catalyses the release of CLIP once an antigenic peptide is present
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 Activated 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
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 & mycobacteria (tuberculosis) 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
Class I requires TAP, Tapasin, etc control
Class II requires low pH for removal of Ii
T-cell dependent B cell response
Sequence of events:
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).
