MICB 212 Chapter 8 Notes

Antigen Processing and Presentation

-antigen presentation is the displaying of peptides derived from pathogens or other proteins on dendritic cell surface that T cells can see

-MHC proteins expressed on cell surface provide physical structure to display antigenic peptides to T cells

Major Histocompatibility Complex (MHC) Proteins

-2 types of MHC proteins

• both proteins have grooves that can bind peptides

MHC Class I Proteins

-expressed on all nucleated cells

-consist of transmembrane α chain that is non-covalently associated with a soluble protein (β2-microglobulin)

-peptide bonding groove located within the α chain

• binds to nascent MHC class I protein

MHC Class II Proteins

-expressed only on antigen-presenting cells (dendritic cells, macrophages, thymic epithelial cells)

-consist of 2 non-identical transmembrane polypeptide chains (α and β chains)

-peptide bonding groove formed between α and β chains

-peptide of at least 13 amino acids in length binds to MHC class II protein

Antigen Processing

• degradation of protein into peptide fragments

Antigen Presentation

• binding and display of antigen as peptide fragment bound to MHC proteins on surface of a cell

-MHC class I proteins display peptides derived from proteins in cytoplasm of cell

• proteins coming from inside of cell

• proteins synthesized by ribosomes

-MHC class II proteins display peptides derived from soluble proteins taken up by a cell via endocytosis or phagocytosis into an endosome or phagosome

• proteins coming from outside of cell

• proteins can include normal blood proteins, toxins, bacteria or virus particles

Pathways for Processing and Presentation of Protein into Peptide Fragments

Endogenous Pathway (MHC Class I Peptide Loading)

-intracellular proteins degraded into peptides by proteasome (protease complex located in cytoplasm)

-transporter proteins called TAP proteins move resulting peptides from cytoplasm to lumen of ER

-peptide binds to nascent MHC class I protein

-MHC class I peptide complexes transported to cell surface

Exogenous Pathway (MHC Class II Peptide Loading)

-MHC class II proteins with associated invariant chain (ii) proteins leave ER in vesicles

-after endocytosis or phagocytosis of bacterium/virus/protein, endosome or phagosome fuses with lysosomes that contain lysozyme, proteases and bactericidal substances

-proteases degrade proteins (bacteria, virus, blood) into peptides

-peptides derived from proteins remain inside vesicles

• don’t enter cell’s cytoplasm

-vesicles containing MHC class II/invariant complexes fuses with vesicles containing peptide fragments in MIIC region of cell

-invariant chain is degraded to a smaller fragment (CLIP) and occupies peptide-binding site

-CLIP replaced with peptide fragment

-MHC class II peptide complexes are transported to cell surface

Cross-Presentation Pathway

-mix of exogenous and endogenous pathways

-MHC class I proteins display peptides derived from exogenous proteins

-dendritic cells aid with cross-presentation

-peptides derived from antigens taken up by cell in an endosome or phagosome and contents of vesicle are diverted to proteasome

-processing of peptides follows endogenous pathway

• dendritic cells present peptides derived from exogenous antigens on both MHC I proteins and MHC class II proteins

MHC Diversity

-goal of MHC protein is to be able to bind and present peptide derived from any protein

• especially foreign proteins from a pathogen

-if unable to present peptides from a pathogen → can’t make adaptive immune response against it

-single MHC protein can bind many but not all peptides

• HLA-A protein might not be able to bind a particular peptide derived from viral pathogen but same peptide might be able to bind to HLA-C protein

  • in this case → cells would use HLA-C protein to present viral peptide to T cells

MHC Genes are Polygenic

-several genes that encode proteins that have a similar function

MHC Genes are Codominantly Expressed

-MHC genes from mother and father will be different alleles

• 2 HLA-A proteins on surface of cells

• 2 HLA-B proteins on surface of cells

• 2 HLA-C proteins on surface of cells

-combination of all HLA proteins expressed defines tissue type → important in organ transplants

MHC Genes are Polymorphic

-different alleles for each MHC gene

-at least 5000 versions of HLA-A gene

-polymorphism of MHC genes is important for survival of any species

-for any given pathogen, some portion of population will be able to present peptides from that pathogen and make an immune response to eliminate the pathogen

-reduction in MHC polymorphism may predispose species to infectious disease

Human MHC Class I Proteins

-3 types of MHC Class I proteins — HLA = human leukocyte antigen

• HLA-A

• HLA-B

• HLA-C

-all proteins are expressed on all nucleated cells

-6 different MHC class I proteins

• 3 (1 HLA-A, 1 HLA-B, 1 HLA-C) from mom

• 3 (1 HLA-A, 1 HLA-B, 1 HLA-C) from dad

Human MHC CLASS II Proteins

-3 types of MHC class II proteins

• HLA-DP

• HLA-DQ

• HLA-DR

-all proteins only expressed on antigen presenting cells

• macrophages

• dendritic cells

• B cells

• thymic epithelial cells

Summary

-MHC proteins expressed on cell surface allows cell to communicate to T cells

-MHC class I proteins consist of membrane-bound chain → non-covalently associated with β2-microglobulin

-MHC class II proteins are dimers of α and β chain

-MHC class I proteins are found on all nucleated cells

-MHC class II proteins are found only on antigen-presenting cells

-antigenic peptides must be processed and loaded onto MHC proteins

• MHC class I proteins use endogenous pathway for peptide loading

  • present peptides derived from proteins made inside cell

• MHC class II proteins use exogenous pathway for peptide loading

  • present peptides derived from extracellular antigens

    • includes proteins taken up by endocytosis or phagocytosis

-cross-presentation occurs when dendritic cells phagocytose a foreign antigen and present it on MHC class I proteins and MHC class II proteins.