Antigen processing and presentation

Three sources of antigen to T cells and on which molecules they are presented on

cytosolic pathogen - degraded in cytosol - on MHC class I

• Normal self proteins: Made by the cell’s own ribosomes as part of normal metabolism.

• Viral proteins: Produced when a virus infects the cell and hijacks its ribosomes to make viral components.

• Mutated or abnormal proteins: From cancerous transformation or defective ribosomal products (DRiPs).

These never “enter” from outside — they’re synthesized in the cytosol.

intravesicular pathogens - degraded in endocytic vesicle - on MHC class II (eg, tuberculosis)

extracellular pathogens and toxins - degraded in endocytic vesicle - on MHC class II

Steps of the endogenous pathway for MHC class I

How peptides sourced form nascent proteins inside the cells are ferried into the ER, where they are combined with the newly synthesized heavy chain of MHC class I and b2 microglobulin

Proteins are ubiquitinated by the UPS, which gets unfolded by the 19S subunit and degraded into the small peptides by the 20S subunit

Special proteosome: immunoproteosome

TAP1 and TAP2 which sits on the ER membrane ferry the peptides from the cytosol to the ER lumen

On the ER membrane:

Partly folded MHC class Ia chains bind to calnexin which inhibits b2m binding

b2m binding to mhc i leads to the release of calnexin and binds to a complex of chaperone proteins (calreticulin, ERp57) and binds to TAP via tapasin

TAP delivers peptide to the ER

The peptide binds MHC I and completes its folding, dissociate from the TAP complex and exported to the cell membrane

Immunoproteosome

gamma interferon (IFNy) induces alternative of the proteosome which alter the components, whilst also increasing the MHCI expression. The immunoproteosomes are very good at creating hydrophobic resides that are preferable for MHC I binding.

Are TAPs ATP dependent?

Yes

What are Drips?

Product after ribosome translation - proteins that are in unfolded conformation, which gets ubiquitinated and cut into peptides that can be expressed on MHC - usually are the dominant and common proteins

MHC class II peptide loading

Peptides sourced via endocytosis, phagocytosis or macrophagocytosis delivered to endosomes in pAPC - macrophage, DC, B cells

Acidification in the endosomes

Acidic cathepsin degrades proteins

MHC class II is first synthesized in the ER with the invariant chain (Ii). When it gets transported to the acidified endosome, Ii is progressively cleaved to a shorter chain (CLIP)

The peptide cannot bind to MHCII due to CLIP, but when HLA -DM /DO binds to MHC class I molecule, releasing CLIP and allow other peptides to bind. MHC II transported to the cell membrane

What is cross-presentation in DC and how it is important in CTL licensing

Certain subsets of DC are efficient in capturing exogenous proteins and allow them to be present on MHCI.

These proteins can enter the phagolysosome and gets degraded in the proteosome, or get directly transported from the phagolysosome into a vesicular loading compartment

Important for CTL to kill other virally infected cells