What is the difference between the class I and class II processing pathways?

The class I pathway degrades proteins from inside the cell using the proteasome and loads peptides in the endoplasmic reticulum, while the class II pathway degrades proteins taken up from outside the cell in endosomes and loads peptides there.

What is cross-presentation?

Cross-presentation is the ability of certain antigen-presenting cells to load externally derived antigens onto MHC class I, allowing them to prime cytotoxic CD8+ T cells against material the cell itself did not produce.

Antigen Processing: Proteasomal and Endosomal Pathways

Antigen processing is the set of cellular events that convert intact proteins into the short peptides that MHC molecules display. Two principal routes operate in parallel: a cytosolic, proteasome-dependent pathway that supplies MHC class I, and an endosomal, protease-dependent pathway that supplies MHC class II. A third route, cross-presentation, lets some cells load extracellular antigens onto class I. Together these pathways determine which peptides the immune system sees.

Definition

Antigen processing is the proteolytic and trafficking machinery that degrades proteins into peptides and delivers them to MHC class I (mainly via the cytosolic proteasome-TAP pathway) or MHC class II (via the endosomal pathway) for surface presentation to T cells.

Scope

This topic covers the proteasomal generation and TAP-dependent transport of class I peptides, the endosomal degradation and HLA-DM-assisted loading of class II peptides, and the concept of cross-presentation. It is reference material on cell biology and does not provide clinical guidance.

Core questions

How does the proteasome generate peptides for MHC class I, and how does TAP move them into the endoplasmic reticulum?
How are endosomal proteases and HLA-DM used to load MHC class II?
What is cross-presentation and why is it important?
How do the two pathways partition self and foreign antigens between class I and class II?

Key concepts

Proteasome and immunoproteasome
Transporter associated with antigen processing (TAP)
Peptide-loading complex
Endosomal and lysosomal proteases
Invariant chain, CLIP, and HLA-DM
Cross-presentation
Cytosolic versus endosomal partitioning

Mechanisms

In the class I (endogenous) pathway, cytosolic proteins are degraded by the proteasome, peptides are pumped into the endoplasmic reticulum by TAP, trimmed by aminopeptidases, and loaded onto class I with help from the peptide-loading complex. In the class II (exogenous) pathway, proteins captured by endocytosis or phagocytosis are degraded in acidic endosomal and lysosomal compartments; class II molecules delivered there shed the invariant chain remnant CLIP under the action of HLA-DM and acquire antigenic peptides. Cross-presentation allows certain antigen-presenting cells, notably some dendritic cells, to route exogenous antigen into the class I pathway, which is important for priming cytotoxic responses to material the presenting cell did not itself synthesise. Reviews integrate these routes and their regulation.

Clinical relevance

Antigen-processing pathways shape immune responses to viruses, tumours, and vaccines, and they are targets of viral immune-evasion strategies and relevant to immunotherapy design. This entry describes the cellular machinery for educational purposes and is not a basis for individual diagnostic or treatment decisions.

Evidence & guidelines

The pathway descriptions rest on peer-reviewed immunology reviews summarising established cell biology rather than clinical guidelines.

History

The recognition in the late twentieth century that MHC molecules present processed peptides, rather than intact antigen, reframed antigen recognition. Discovery of the proteasome's role and of TAP explained how class I peptides are produced and delivered, while work on the invariant chain and HLA-DM clarified the endosomal class II route. Cross-presentation was later established as a distinct capability of specialised antigen-presenting cells, and reviews now treat the pathways as an integrated system.

Key figures

Peter Cresswell
Jacques Neefjes
Paul Roche

Seminal works

blum-2013
neefjes-2011
roche-2015

Frequently asked questions

What is the difference between the class I and class II processing pathways?: The class I pathway degrades proteins from inside the cell using the proteasome and loads peptides in the endoplasmic reticulum, while the class II pathway degrades proteins taken up from outside the cell in endosomes and loads peptides there.
What is cross-presentation?: Cross-presentation is the ability of certain antigen-presenting cells to load externally derived antigens onto MHC class I, allowing them to prime cytotoxic CD8+ T cells against material the cell itself did not produce.