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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).