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Cross-presentation, in immunology, is the process by which antigen-presenting cells take up extracellular or phagocytosed antigens and present them on major histocompatibility complex (MHC) class I molecules to CD8+ T cells. This differs from the classic endogenous pathway, where intracellular proteins are processed for MHC I presentation. Cross-presentation enables naive CD8+ T cell activation against pathogens or tumor antigens that do not infect antigen-presenting cells directly.

There are two main pathways. The cytosolic pathway involves translocation of internalized antigen from the phagosome into the cytosol, where it is degraded by the proteasome. Resulting peptides are transported by TAP to MHC I molecules in the endoplasmic reticulum or phagosomal compartments for loading and surface presentation. The vacuolar pathway processes and loads peptides onto MHC I within the phagosome itself, with little or no involvement of the cytosol or proteasome.

Conventional dendritic cells are the most proficient cross-presenters, particularly the CD8α+ subset in mice and their human equivalents (BDCA-3+ or CD141+ dendritic cells). Other antigen-presenting cells, including some macrophages and B cells, can cross-present but typically with lower efficiency. Uptake receptors such as DEC-205 and CLEC9A can direct antigens toward the cross-presentation pathway.

Cross-presentation underpins cross-priming, the activation of naive CD8+ T cells by cross-presented antigens, leading to cytotoxic T cell responses. It has significant implications for vaccine design and cancer immunotherapy, where boosting cross-presentation can enhance CTL-mediated immunity against infections and tumors.