Antigen Processing and Cross‐Presentation


The human immune system has evolved to defend us from infections by a diverse array of pathogens. To achieve such a feat – especially in the face of species capable of fare, more rapid evolution than ourselves – it has evolved a two‐tiered defence system consisting of an innate part, which has evolved to recognise and respond to evolutionary conserved molecular patterns for which evolution is very slow, and an adaptive part, which has the ability to respond to specific molecular patterns on specific pathogens and can tailor the response against the pathogen. These two branches of the immune system are in intimate interplay: A key information transfer event between the innate and the adaptive immune system is the process by which phagocytic immune cells capture, process and present antigens and peptides from the pathogenic proteome to the body's diverse population of T cells. Recognition of these peptides by specific T cells results in their activation and not in the activation of T cells that are not capable of recognising the pathogenic peptides. This activation leads to T cells activating and adopting its role as orchestrator/executioner in the antipathogen response and is thus a pivotal event in host defence.

Key Concepts

  • Antigen‐presenting cells take up antigen through endo‐, phago‐ and macropinocytosis.
  • This material is subjected to a host of degradative enzymes. The proteases found in the endolysosomal system hydrolyse the protein content of the material that was taken up.
  • Peptides resulting from this degradation can be loaded onto MHC‐II complexes (which are themselves converted to a peptide‐receptive state by lysosomal proteases), resulting in the activation of CD4+ helper T cells.
  • Not all resulting peptides are loaded onto MHC‐II complexes. A certain proportion of peptides is also loaded on MHC‐I complexes for activating CD8+ cytotoxic T cells, which is one of the key steps in the immune‐mediated clearance of tumours and virus‐infected cells.
  • These MHC‐I complexes normally reside in the endoplasmic reticulum. This presents a trafficking problem: how does endolysosomally located material encounters a peptide complex that is resident in ER?
  • A wide variety of routing options have been proposed by which this class of antigenic peptide can reach and be loaded onto MHC‐I, such as routes via the cytosol, via ER‐vesicle fusion and many others.

Keywords: antigen presentation; antigen cross‐presentation; proteolysis; T‐cell activation

Figure 1. Schematic representation of antigen processing (peptide editing and loading), routing and presentation during MHC class I antigen presentation pathway.
Figure 2. Certain positions are a key for anchoring to MHC‐I and others are key to T‐cell recognition. Two dominant H2‐Kb anchor positions: phenylalanine (F) or tyrosine (Y) at position 5 (P5) and leucine (L) or methionine (M) at position 8 (P8), whereas positions 4, 6 and 7 are T‐cell binding determinants.
Figure 3. Schematic representation of antigen processing (peptide editing and loading), routing and presentation during MHC class II antigen presentation pathway.
Figure 4. Schematic representation of the intracellular pathways operating throughout the cytosolic and vacuolar cross‐presentation pathways (gap junction‐mediated peptide transfer not shown).
Figure 5. Schematic representation of the FRET‐based‐β‐lactamase assay used to evaluate endosomal export to the cytosol.


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Further Reading

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Pawlak, Joanna B, and van Kasteren, Sander I(Oct 2017) Antigen Processing and Cross‐Presentation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027590]