crosspresenting

Crosspresenting, more commonly referred to as cross-presentation, is the process by which professional antigen-presenting cells, especially dendritic cells, present exogenous protein antigens on MHC class I molecules to CD8+ T cells. This mechanism enables the priming of cytotoxic T cell responses against pathogens and tumors that do not directly infect antigen-presenting cells.

There are two major pathways. In the cytosolic pathway, exogenous antigen is translocated into the cytosol, degraded by the proteasome, and peptide fragments are transported into the endoplasmic reticulum by TAP for loading onto MHC class I molecules. In the vacuolar pathway, processing and loading occur within endosomal compartments, largely independent of proteasomes and TAP. The relative contribution of these pathways can vary with antigen type, source, and the dendritic cell subset involved. Some components, such as Sec61, are implicated in the transfer of antigen from endosomes to the cytosol, while other chaperones assist in MHC I loading.

Specialized dendritic cell subsets drive crosspresentation. In mice, CD8α+ dendritic cells are particularly proficient, while in humans BDCA-3 (CD141)+ dendritic cells are enriched for this function. Other antigen-presenting cells, including certain macrophages and B cells, can cross-present under specific conditions but are generally less efficient. Effective crosspresentation often requires uptake of antigen by phagocytosis or receptor-mediated endocytosis and appropriate maturation signals.

Crosspresentation is essential for initiating CD8+ T cell responses to viruses and intracellular bacteria that do not infect dendritic cells directly and to tumor-associated antigens. It influences vaccine efficacy and anti-tumor immunity, and deficits in crosspresentation can dampen cytotoxic responses. Regulation involves antigen form, inflammation, and signaling through innate receptors, with implications for immunotherapies and vaccine design.