Antigen Processing

Abstract

Antigen presentation is an important mechanism by which the immune system recognises infection and maintains self‐tolerance. In order to effectively present antigens to T lymphocytes, intracellular enzymes degrade antigenic macromolecules into short fragments, which then bind major histocompatibility complex class I and class II molecules, or alternatively nonpolymorphic major histocompatibility complex class Ib molecules. This process of fragmentation is known as antigen processing and is shaped by the specificity of the enzymes involved as well as the intracellular compartments where processing takes place. Key players in antigen processing include cytoplasmic enzymes such as the proteasome and calpain, as well as cysteine cathepsins, aspartyl proteases, NADPH oxidase and GILT, which all reside in acidic vacuolar compartments. The trafficking of antigens to different intracellular compartments influences the sequence of processing and the selection of antigenic epitopes, which are displayed on the cell surface to promote immune activation or tolerance.

Key Concepts

  • Trafficking of antigens into proper compartments affects the degradation and availability of epitopes for both MHC‐I and MHC‐II presentation.
  • Proteasome activity affects MHC‐I peptide generation and endogenous cytoplasmic peptide generation for MHC‐II.
  • ROS production by NADPH oxidase can affect MHC‐I cross‐presentation and MHC‐II presentation.
  • Cathepsin activity, which is regulated by endosomal pH, generates peptides for MHC‐I cross‐presentation and MHC‐II presentation.
  • The reduction of disulphide bonds by GILT affects availability of epitopes for MHC‐II presentation.
  • While homologous to MHC‐I, nonclassical MHC‐Ib acquire antigens processed in acidic compartments much like MHC‐II.

Keywords: MHC‐I; MHC‐II; CD1; antigen trafficking; antigen processing; antigen presentation

Figure 1. The proteasome. The proteasome is an enzyme complex located in the cytosol that is involved in multiple cellular processes including the production of peptide ligands for MHC‐I. (a) The 20S proteasome consists of four stacked rings. The outer two rings consist of seven α subunits, while the inner two rings consist of seven β subunits. The catalytic subunits are β1, β2 and β5. (b) The 20S proteasome can associate with two 19S regulatory complexes to form the 26S proteasome. Protein substrates are preferentially targeted to the 26S proteasome by polyubiquitination. (c) The cytokine IFN‐γ induces the expression of the alternative β subunits LMP‐2, MECL‐1 and LMP‐7, which can replace β1, β2 and β5, respectively. The resultant structure is known as the immunoproteasome. This structure generates an increased number of peptides capable of binding MHC‐I. IFN‐γ can also induce the expression of another regulatory subunit (PA28 or 11S), which can replace the 19S regulatory subunits, thus further diversifying the repertoire of epitopes available for MHC‐I binding.
Figure 2. MHC‐I antigen presentation pathways. Before being loaded onto MHC‐I, endogenous antigens are degraded into peptides by the proteasome. These peptides are then translocated from the cytoplasm into the ER by TAP. In the ER, MHC‐I fold and associate with tapasin, which links MHC‐I with TAP. Tapasin and chaperones together with MHC‐I form the peptide‐loading complex (PLC), which facilitates peptide binding to receptive MHC‐I. Within the ER, peptides can be further trimmed at the N‐terminus by ERAPs. Peptide:MHC‐I complexes are then shuttled through the Golgi to the cell surface where they interact with CD8+ T cells. MHC‐I can also associate with peptides derived from exogenous antigens in a process known as cross‐presentation. Processing of exogenous antigens for cross‐presentation can take place in phagosomes or within the cytoplasm.
Figure 3. NADPH oxidase activity modulates antigen processing. (a) The NADPH oxidase enzyme complex assembles on the phagosome membrane in dendritic cells, and loss of NADPH oxidase activity results in increased proteolysis of phagocytosed antigens. Some studies have shown that this increase in antigen proteolysis is associated with an increase in phagosome acidification, while others suggest that it is associated with increased levels of cysteine cathepsin activity, independent of pH. Nonetheless, this increase in antigen proteolysis results in the destruction of MHC‐I epitopes and less efficient cross‐presentation. (b) NADPH oxidase activity has also been shown to modulate MHC‐II antigen presentation; however, the location of the enzyme complex in relation to MHC‐II antigen processing is not clear. Lack of NADPH oxidase activity has been associated with the increased cleavage of specific MHC‐II epitopes owing to increased cysteine cathepsin activity and the preferential presentation of membrane‐associated antigens. Overall, lack of NADPH oxidase activity results in an altered repertoire of MHC‐II epitopes.
Figure 4. MHC‐II antigen presentation pathways. Exogenous antigens are internalised via clathrin‐mediated endocytosis and subsequently delivered to the endosomal–lysosomal network for processing by proteases, reductases and potentially other enzymatic and nonenzymatic processes. Endogenous antigens can also enter this network through macroautophagy (MA) and chaperone‐mediated autophagy (CMA). Processing reactions within the endosomal–lysosomal network give rise to antigenic peptides or epitopes, which can intersect MHC‐II molecules in route to the cell surface. Newly synthesised MHC‐II assemble and associate with the chaperone Ii in the ER. The MHC‐II:Ii complexes are then sorted through the Golgi and into the endosomal–lysosomal network. Lysosomal proteases sequentially cleave Ii, leaving the Ii fragment CLIP in the MHC‐II peptide‐binding groove. HLA‐DM catalyses the removal of CLIP and facilitates binding of antigenic peptides. MHC‐II:peptide complexes are then shuttled to the surface to be displayed for recognition by CD4+ T cells.
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Further Reading

Murphy K, Travers P, Walport M, et al. (2012) Janeway's Immunobiology, 8th edn. London and New York: Current Biology‐Garland Science.

Parham P and Janeway C (2014) The Immune System, 4th edn. London and New York: Current Biology‐Garland Science.

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Gardiner, Gail J, Deffit, Sarah N, and Blum, Janice S(Sep 2015) Antigen Processing. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001228.pub3]