B Cell Receptors and Complement Receptors Target the Antigen to Distinct Intracellular Compartments

Abstract

The processing of exogenous Ags is an essential step for the generation of immunogenic peptides that will be presented to T cells. This processing relies on the efficient intracellular targeting of Ags, because it depends on the content of the compartments in which Ags are delivered in APCs. Opsonization of Ags by the complement component C3 strongly enhances their presentation by B cells and increases their immunogenicity in vivo. To investigate the role of C3 in the targeting of Ags, we compared the intracellular traffic of proteins internalized by complement receptor (CR) and B cell receptor (BCR) in B lymphocytes. Whereas both receptors are able to induce efficient Ag presentation, their intracellular pathways are different. CR ligand is delivered to compartments containing MHC class II molecules (MHC-II) but devoid of transferrin receptor and Lamp-2, whereas BCR rapidly targets its ligand toward Lamp-2-positive, late endosomal MHC-II-enriched compartments through intracellular vesicles containing transferrin receptor. CR and BCR are delivered to distinct endocytic pathways, and the kinetic evolution of the protein content of these pathways is very different. Both types of compartments contain MHC-II, but CR-targeted compartments receive less neosynthesized MHC-II than do BCR-targeted compartments. The targeting induced by CR toward compartments that are distinct from BCR-targeted compartments probably participates in C3 modulation of Ag presentation.

Antibody-Mediated Immunomodulation: a Strategy To Improve Host Responses against Microbial Antigens

“…MHC class II antigen presentation is influenced by the endocytic compartment used for processing of internalized antigen. Opsonization of antigen by C3b and uptake via complement receptors have now been shown to alter intracellular trafficking of internalized antigen compared to uptake via the B-cell receptor in B lymphocytes (88). Again, the resultant change in epitopes favored for display to CD4 T cells by MHC class II would ultimately influence the nature and specificity of the elicited response.…”

Dendritic Cell-Lysosomal-Associated Membrane Protein (LAMP) and LAMP-1-HIV-1 Gag Chimeras Have Distinct Cellular Trafficking Pathways and Prime T and B Cell Responses to a Diverse Repertoire of Epitopes

“…Also, endogenous proteins have been shown to be processed and presented by MHC class II (MHC II) molecules (8). APCs have a variety of specialized Ag uptake mechanisms that capture and transport the Ags to specific endocytic subcompartments (9,16,17), which contain distinct groups of chaperone molecules and proteases (18 -21). For example, cathepsins B and Z have been shown to be present in early and late endosomes but absent from lysosomes, whereas cathepsin D is present in lysosomes and late endosomes (18,19).…”

A new role for complement C3: Regulation of antigen processing through an inhibitory activity

“…Here, we provide direct evidence for the control of Ag proteolysis by C3c, which could be related to the previously described C3-mediated enhancement of Ag presentation and, more generally, of the establishment of a specific immune response. C3 is therefore directly involved in Ag degradation by APC through at least two distinct mechanisms: i) C3b modulates Ag trafficking within the APC ( ) thereby potentially affecting Ag processing through modified protease activities Perrin-Cocon et al, 2004 located within the intracellular compartments, and ii) C3 directly inhibits Ag proteolysis by lysosomal proteases, as illustrated by our results. The C3 present in APC could be of extracellular origin, via C3b binding to exogenous Ag, as well as of intracellular origin, since C3 is synthesized by various APC such as dendritic cells ( ) or macrophages ( ).…”

“…LF was characterized as previously described ( ) and stored at 80 Villiers et al, 1996Perrin-Cocon et al, 2004 −°C until use.…”