Lecture 8 - MHC Complex: Antigen Processing and Presentation

• MHC class I proteins

  Have 2 subunits: MHC class I alpha chain encoded in MHC cluster and beta2 microglobulin (B2M) encoded elsewhere in the genome
• MHC class I proteins

  • Peptide-binding groove formed by alpha chains alpha1 and alpha2 domains
  • Extensive polymorphism in alpha chain, whereas B2M is invariant
  • Peptides derived from cytosolic proteins, typically 8-10 amino acids in length, are presented by MHC class I to CD8 T cells
  • MHC-I binds ends of peptide, and the peptide-binding groove has bulky conserved amino acid side chains (tyrosine residues) that interact with the peptide, stopping MHC I from binding peptides that are longer than 8-10 amino acids
• MHC class II proteins

  • Also has 2 subunits similar to MHC-I
  • Both alpha chain and beta chain are encoded in the MHC cluster
  • Peptide-binding groove formed by alpha1 and beta1 domains
  • Extensive polymorphism in both alpha chain and beta chain
  • Peptides derived from extracellular or vesicular proteins, typically 13 or more amino acids in length, are presented by MHC class II to CD4 T cells
  • MHC class II has a more open peptide-binding groove, allowing longer peptides to protrude from either end
• MHC polymorphisms and polygeny

  • The greatest MHC polymorphisms are found in the peptide-binding groove, where distinct pockets form to fit anchor residues, allowing different MHC molecules to bind to different peptides
  • This diversity in MHC polymorphisms makes it difficult for pathogens to evolve to be "non-presentable" due to the specific binding of anchor residues
  • MHC polygeny ensures efficient presentation by allowing each person to express several different variants of MHC class I and class II genes, resulting in a large number of distinct alleles in the human population
• MHC class I presents peptides derived from cytosolic proteins to CD8 T cells


  MHC class II presents peptides derived from extracellular or vesicular proteins to CD4 T cells
• How MHC class I presents peptides from cytosolic proteins

  1. Digestion of cytosolic proteins by the proteosome

  2. Transport of peptides into the endoplasmic reticulum (ER) by the Transporters associated with Antigen Processing (TAP) proteins

  3. Peptide loading onto MHC class I, where stable peptide binding is essential for cell surface MHC expression
• How MHC class II presents peptides from exogenous proteins

  1. Peptides are generated in acidified endosomes, where acid pH activates acid cysteine proteases (cathepsins)

  2. MHC-II protein is co-translationally translocated into the ER membrane, where the invariant chain (CD74) blocks the peptide-binding groove and directs MHC-II from the ER to acidified endosomes

  3. In the acidified endosomes, the invariant chain is cleaved to CLIP, and HLA-DM promotes stable peptide binding
• Cross-presentation


  • Dendritic cells express endosomal channel protein, called Sec61, which shuttles peptides from the MHC class II pathway into the cytosol, promoting cross-presentation
  • Cross-presentation allows dendritic cells to present exogenous antigens on MHC class I, activating naive CD8 T cells, even if the virus does not directly infect the dendritic cells
• Cross-presentation is essential for activating naive CD8 T cells against viruses that do not directly infect dendritic cells
• Cross-presentation plays a key role in the activation of CD8 cytotoxic T cells, which are crucial for eliminating infected cells and controlling viral infections
• Cross-presentation ensures that a broad range of antigens can be presented to the immune system, enhancing the overall effectiveness of the adaptive immune response