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Antigen presentation pathways process antigens into peptides and load them onto MHC molecules. The MHC-I pathway (proteasomal degradation) handles intracellular antigens; the MHC-II pathway (endosomal degradation) handles exogenous antigens. Cross-presentation allows dendritic cells to present exogenous antigens on MHC-I, linking innate and adaptive responses.
From your study of MHC structure and function, you know that MHC molecules display peptide fragments on the cell surface for T cell recognition. But MHC molecules do not simply grab whole proteins and show them — there are elaborate intracellular processing pathways that chop proteins into peptides and load them onto the correct MHC class. The antigen processing and presentation pathways are the machinery that converts raw protein antigens into the peptide-MHC complexes that T cells actually see. Understanding these pathways explains why CD8+ T cells detect infections inside cells while CD4+ T cells respond to threats captured from outside.
The MHC class I pathway handles intracellular antigens — proteins made within the cell, including viral proteins during infection. These proteins are tagged with ubiquitin and fed into the proteasome, a barrel-shaped protease complex in the cytoplasm that chops them into short peptides (typically 8–10 amino acids). These peptides are then shuttled into the endoplasmic reticulum by the TAP transporter (Transporter associated with Antigen Processing), where they are loaded onto newly synthesized MHC-I molecules with the help of chaperones like tapasin. The loaded MHC-I complex then travels through the Golgi to the cell surface. Because virtually all nucleated cells express MHC-I and continuously sample their own cytoplasmic proteins through this pathway, any cell that becomes infected will inevitably display foreign viral peptides — flagging itself for destruction by CD8+ cytotoxic T cells.
The MHC class II pathway handles exogenous antigens — proteins captured from outside the cell through endocytosis or phagocytosis. Professional antigen-presenting cells (dendritic cells, macrophages, B cells) internalize extracellular material into endosomes, which progressively acidify and activate cathepsin proteases that degrade the captured proteins into peptides. Meanwhile, MHC-II molecules are synthesized in the ER with a protective invariant chain (Ii) that blocks the peptide-binding groove, preventing premature loading of ER-resident peptides. The MHC-II–invariant chain complex travels through the Golgi to merge with the endosomal compartment. There, cathepsin S cleaves the invariant chain, leaving a small fragment called CLIP in the groove, which is then exchanged for an antigenic peptide with the help of the HLA-DM chaperone. The loaded MHC-II complex reaches the cell surface to activate CD4+ helper T cells.
There is one critical exception to the neat division of "MHC-I for internal, MHC-II for external." Cross-presentation is the ability of certain dendritic cells to take exogenous antigens — captured from outside — and route them into the MHC-I pathway instead. This is immunologically essential: if a virus infects a tissue cell that is poor at activating T cells, the immune system needs a way for professional antigen-presenting cells to acquire that viral material and present it on MHC-I to prime naïve CD8+ T cells. Cross-presentation solves this problem, bridging the innate capture of extracellular debris with the adaptive cytotoxic response. Without it, the immune system would struggle to mount CD8+ responses against many viruses and tumors.