MHC Class II Molecules & Antigen Processing

• The immune system uses different strategies to eliminate pathogens replicating intracellularly.

MHC Class II Molecules

• MHC class II molecules present peptides from the vesicular system to the surface, recognized by CD4+ T cells.
• Exogenous antigen processing is understood primarily through experiments using macrophages fed with antigens.
• Antigen presenting cells engulf or are invaded by pathogens which starts antigen processing in an acidified endocytic vesicle.

Antigen Processing Pathways

• Endogenous (cytosolic) antigen processing involves ubiquitin and the proteasome complex.
• Exogenous (endocytic) antigen processing involves phagocytosis.

Exogenous Antigen Processing

• MHC class II molecules assemble with an invariant chain in the endoplasmic reticulum (ER).
• The invariant chain prevents other peptides from binding to the MHC during transport.
• The MHC class II complex with the invariant chain exits the ER in a vesicle.
• The invariant chain degrades into smaller pieces called CLIP.
• CLIP (Class II-Associated Invariant Chain Peptide) temporarily blocks the peptide-binding site on the MHC class II molecule.
• Antigen-Presenting Cells (APCs) capture microbes via phagocytosis or endocytosis.
• Microbes are broken down inside phagolysosomes, formed by merging vesicles with lysosomes.
• The vesicle carrying the MHC class II complex fuses with the phagolysosome.
• Antigenic peptides replace CLIP on the MHC class II molecule.
• The MHC class II-peptide complex goes to the APC's cell surface.
• The complex presents the antigen to CD4+ T helper cells, triggering immune responses and activating B cells or macrophages.

MHC Class I Molecules

• Deliver peptides from the cytosol to the cell surface and present antigenic peptides to CD8 positive T cells.
• Fragments that bind to MHC class I molecules are often from viruses.
• Some bacteria replicate in the cytosol and the antigens are presented by MHC class I molecules to CD8 positive T cells.

Endogenous Antigen Processing

• After entry, pathogens are tagged with ubiquitin for proteolytic degradation by the proteasome complex.
• Transporters associated with antigen processing (TAP) load peptides onto class I MHC molecules.
• Antigenic peptide binding to the MHC molecule facilitates transport out of the rough ER, through the Golgi apparatus, to the cell surface.

Endogenous Pathway

• MHC class I molecules use the endogenous pathway of antigen presentation.
• Cellular proteins are marked for degradation and sent to the proteasome.
• The proteasome degrades proteins into short peptide chains.
• Transporters of antigenic peptides (TAP) transport short peptide chains to the endoplasmic reticulum.
• MHC class I molecules (alpha chain and beta-2 microglobulin) are also made in the endoplasmic reticulum.
• TAP proteins load short peptide chains onto the MHC class I molecule using tapasin.
• The MHC class I molecule and peptide move from the endoplasmic reticulum through the Golgi apparatus to the cell surface.
• Cytotoxic T cells and natural killer cells interact with the MHC class I molecule and the antigen.
• If the peptide is recognized as foreign, the cell is attacked, if nothing is recognized, the cell lives.

Exogenous Pathway

• The exogenous pathway begins when a pathogen or protein is ingested by an antigen presenting cell, then brought into a vacuole called the endosome.
• Granules in the phagocyte fuse with the endosome, creating a phagosome or phagolysosome.
• Granules contain proteolytic and degrading enzymes, which degrade the pathogen or protein into many small peptides.
• MHC class II molecules are generated in the ER with other host proteins (including MHC class I).
• Instead of getting its peptide from within the ER, the MHC class II molecule's binding cluster groove is temporarily filled by the invariant chain.
• The MHC class II molecule and invariant chain are transported through the cell in a vesicle where the invariant chain is degraded.
• The vesicle with the MHC class II molecule fuses with the phagosome and lysosome; the peptide quest is filled by one of the peptides residing in the phagolysosome.
• This vesicle now contains the MHC class II molecule bound to the peptide antigen goes to the cell surface where it presents to circulating helper T cells, and stimulation of the immune system occurs.

Endogenous vs Exogenous Antigen Processing

Endogenous Antigen Processing (MHC Class I Pathway):

• Presents antigens from intracellular sources, such as viruses or tumor cells.
• Intracellular proteins are broken down into short peptide fragments by the proteasome.
• Peptides go to the ER using transporter associated with antigen processing (TAP) proteins.
• In the ER, peptides are loaded onto MHC class I molecules
• MHC class I-peptide complexes move to the cell surface, and CD8+ cytotoxic T cells recognize them.
• Elimination of infected or abnormal cells will occur.

Exogenous Antigen Processing (MHC Class II Pathway):

• Presents antigens from extracellular sources (bacteria or fungi).
• Antigen-presenting cells (APCs) uptake extracellular proteins (macrophages, dendritic cells, or B cells) through phagocytosis or endocytosis.
• Proteins are broken down into peptide fragments within vesicles or lysosomes.
• MHC class II molecules bind to the peptide fragments.
• MHC class II-peptide complexes moving to the cell surface where CD4+ helper T cells recognize it.
• This essential for coordinating the immune response by activating other immune cells.

Tumor Antigens, Cytosolic and Endocytic Pathways

• Antigen Source: Cytosolic Pathway (endogenous): Intracellular proteins, Endocytic Pathway (exogenous): Extracellular proteins and pathogens
• Processing Location: Cytosolic Pathway: Proteasome and ER, Endocytic Pathway: Endosomes and lysosomes
• MHC Molecule Involvement: Cytosolic Pathway: MHC class I, Endocytic Pathway: MHC class II
• T Cell Recognition: Cytotoxic T Cells (CD8+): Recognize MHC class I-peptide complexes, Helper T Cells (CD4+): Recognize MHC class II-peptide complexes