The Other Function: Class II-Restricted Antigen Presentation by B Cells

Abstract

Mature B lymphocytes (B cells) recognize antigens using their B cell receptor (BCR) and are activated to become antibody-producing cells. In addition, and integral to the development of a high-affinity antibodies, B cells utilize the specialized major histocompatibility complex class II (MHCII) antigen presentation pathway to process BCR-bound and internalized protein antigens and present selected peptides in complex with MHCII to CD4+ T cells. This interaction influences the fate of both types of lymphocytes and shapes immune outcomes. Specific, effective, and optimally timed antigen presentation by B cells requires well-controlled intracellular machinery, often regulated by the combined effects of several molecular events. Here, we delineate and summarize these events in four steps along the antigen presentation pathway: (1) antigen capture and uptake by B cells; (2) intersection of internalized antigen/BCRs complexes with MHCII in peptide-loading compartments; (3) generation and regulation of MHCII/peptide complexes; and (4) exocytic transport for presentation of MHCII/peptide complexes at the surface of B cells. Finally, we discuss modulation of the MHCII presentation pathway across B cell development and maturation to effector cells, with an emphasis on the shaping of the MHCII/peptide repertoire by two key antigen presentation regulators in B cells: HLA-DM and HLA-DO.

Keywords: B cell; HLA-DM; HLA-DO; MHC class II; antigen presentation; antigen processing; germinal center; invariant chain.

Figure 1

Current model of the regulation of antigen processing and presentation in B cells. B cell antigen uptake by membrane immunoglobulin (mIg) is substantially (1,000×) more efficient than by fluid-phase endocytosis. Binding to mIg protects regions of antigens from proteolysis at the early stages of the endocytic pathway. As pH decreases along this pathway, Ig can be processed into antigen-binding fragment (Fab) and crystallizable fragment (Fc) domains. Antigens become available for peptide generation through a combination of unfolding, proteolytic processing, and release from Ig. MHCII/invariant chain (Ii) complexes, DM and its inhibitor, DO, are generated in the endoplasmic reticulum (ER) and transported through the Golgi to late endosomal compartments, termed MIIC. Although Ii processing begins as MHCII/Ii complexes traverse earlier endocytic compartments, exchange of the final Ii remnant peptides (CLIP) bound to the MHCII peptide binding groove with antigenic peptides or self-peptides is inefficient before MHCII enters MIIC. Mechanisms limiting peptide exchange until this stage include (1) DO significantly inhibits DM catalysis of peptide loading and (2) Fab-associated antigen fragments are largely protected from proteolysis to peptides. At late stages of these pathways, lysosomes merge with MIIC. This generates the highly acidic condition that favors denaturation and degradation of DO and Fab, and DM-mediated peptide exchange. Most derivatives of self-proteins internalized without mIg cannot survive endosomal/lysosomal proteolysis. Arrows indicate protein trafficking through different intracellular compartments (indicated by colors) along each pathway. Dotted lines indicate unfavorable processes. ECF, extracellular fluid; MHCII, major histocompatibility complex class II proteins; MIIC, MHCII compartments; CLIP, class II invariant-chain-derived peptides.

Figure 2

Expression of components of the major histocompatibility complex class II (MHCII) antigen presentation pathway across the stages of B cell development. Early B cells (pro-B, pre-B, and immature-B-cell) reside in the bone marrow. These stages are defined by the rearrangement of V, D, and J gene segments at the Ig heavy and light chain loci. At the pre-B cell stages, the pre-BCR is composed of a heavy chain paired with the surrogate light chain (λ 5-Vpre-B), together with signaling components Ig-α and Ig-β. The mature IgM-B cell receptor (BCR) emerges on immature B cells that exit the BM. They migrate to the spleen as transitional B cells and mature to naïve, pre-immune cells of the follicular (FO) B subset, found in the blood and secondary lymphoid organs. Upon immunological challenge, naïve FO B cells that successfully process and present MHCII-bound antigen to CD4+ T cells, differentiate into centroblasts and centrocytes organized in germinal centers. Following BCR affinity maturation, selected B cells further differentiate into long-lived memory B cells or antibody-secreting plasma cells. Relative expression of the MHCII antigen presentation machinery components is represented by color intensity.