Early BCR Events and Antigen Capture, Processing, and Loading on MHC Class II on B Cells

Abstract

B cells are efficient antigen-presenting cells (APCs), relying on antigen uptake through the B cell receptor (BCR). The mechanism of antigen recognition remains a topic of debate; while the prevalent view holds that antigens need to be multivalent for BCR activation, monovalent antigens can also initiate B cell responses. In this review, we describe the steps required for antigen uptake, processing, and loading of peptides onto MHC Class II compartments in B cells for efficient presentation to CD4 T cells, with a special focus in the initial steps of BCR recognition of antigen.

Keywords: B cell receptor; B cells as APC; antigen presentation by B cells; antigen recognition by BCR; antigen valency.

Figure 1

Monomeric antigen can induce BCR cross-linking and activation as long as a signaling threshold is attained. (A) OB1 B cells bear a BCR specific for ovalbumin (OVA), and activation and cross-linking is produced upon interaction with a 17-mer peptide containing the OB1 epitope and an essential FGD sequence. As the size of the peptide including the FGD sequence decreases, so does the ability to induce signal: an 8-mer peptide fails to produce above-threshold signals and it is suboptimal; a 4-mer peptide (GFGD) fails to induce any signal. (B) Reagents directed to the constant region of IgG (such as anti-IgG or anti-kappa) cross-link the BCR by bringing BCRs in close apposition, a similar effect is produced upon chemical conjugation of 8-mer to produce dimers that can now induce significant (above-threshold) BCR signaling.

Figure 2

Events that lead to antigen uptake by the BCR, loading onto MHC Class II and presentation to CD4 T cells. BCR interacts with soluble antigen, or antigen presented by follicular dendritic cells (FDC), macrophages or dendritic cells at the immunological synapse (IS), leading to signaling events (red arrow), antigen-BCR complex uptake and translocation to multi-vesicular bodies (MVB). There, proteases cleave antigen into peptides that are loaded onto MHC Class II; H2/HLA-DM (DM) mediates the removal of the class II-associated peptide (CLIP) which prevents MHC Class II premature loading. H2/HLA-DO (DO) regulates DM. In these compartments, BCR signaling continues (red arrow). B cells also recruit and secrete MHC II-lysosomes to the IS space in a polarized fashion, lowering the pH and facilitating removal of antigen or proteolysis. Peptide-MHC II complexes are then transported to the cell surface for presentation to CD4 T cells.