Long before its role in priming T-cell responses to viruses was appreciated, cross-presentation was observed in studies of minor histocompatibility antigens. These are non-MHC gene products that can elicit strong responses between mice of different genetic backgrounds. When spleen cells from B10 mice of MHC type H-2b were injected into BALB mice of MHC type H-2b×d (which express both b and d MHC types), BALB mice generated cytotoxic T cells reactive against minor antigens of the B10 background. Some of these cytotoxic T cells recognized minor antigens presented by the H-2b B10 cells used for immunization, as one might expect from direct priming of T cells by the B10 antigen-presenting cells. But other cytotoxic T cells recognized minor B10 antigens only when presented by cells of the H-2d MHC type. This meant that these CD8 T cells had been activated in vivo by recognizing the minor B10 antigens presented by the BALB host’s own H-2d molecules. In other words, the minor histocompatibility antigens must have become transferred from the original immunizing B10 cells to the BALB host’s dendritic cells and processed for MHC class I presentation. We now know that cross-presentation by MHC class I molecules occurs not only for antigens on tissue or cell grafts, as in the original experiment described above, but also for viral and bacterial antigens.
It appears that the capacity for cross-presentation is not equally distributed across all antigen-presenting cells. While still an area of active study, it seems that cross-presentation is most efficiently performed by certain subsets of dendritic cells that are present in both humans and mice. Dendritic cell subsets are not identified by the same markers in humans and mice, but in both species, one strongly cross-presenting dendritic cell subset requires the transcription factor BATF3 for its development, and these cells uniquely express the chemokine receptor XCR1. In lymphoid tissues such as the spleen, this lineage of dendritic cells expresses the CD8α molecule on the cell surface, and migratory dendritic cells in lymph nodes capable of cross-presentation are identified by their expression of the αE integrin (CD103). Mice lacking a functional BATF3 gene lack these types of dendritic cells and are also unable to generate normal CD8 T-cell responses to many viruses, including herpes simplex virus.
The biochemical mechanisms enabling cross-presentation are still unclear, and there may be several different pathways at work. It is not clear whether all proteins captured by phagocytic receptors and taken into endosomes need to be transported into the cytosol and degraded by the proteasome in order to be cross-presented. Some evidence supports a direct pathway in which the PLC is transported from the endoplasmic reticulum to the endosomal compartments, allowing exogenous antigens to be loaded onto newly synthesized MHC class I molecules in phagosomes (see Fig. 6.3). Another pathway of cross-presentation by dendritic cells may involve an interferon-γ-induced GTPase known as IRGM3 (short for immune-related GTPase family M protein 3). IRGM3 interacts with adipose differentiation related protein (ADRP) in the endoplasmic reticulum and regulates the generation of neutral lipid storage organelles called lipid bodies, which are thought to originate from ER membranes. Dendritic cells from mice lacking IRGM3 are selectively deficient in cross-presentation of antigens to CD8 T cells, but have a normal process for presenting antigens on MHC class II molecules. The relationship between this and other pathways remains an area of active research.
6-6 Peptide:MHC class II complexes are generated in acidified endocytosis, phagocytosis, and autophagy.