B Cell Responses: Cell Interaction Dynamics and Decisions

Abstract

B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.

Keywords: B lymphocyte; BCR; T-cell help; allergy; antibody; germinal center; isotype switching; lymph node; plasma cell; vaccine.

Figure 1.. The many possible functions of a B cell.

Right side (blue arrows) shows physiological actions and left side (black arrows) shows therapeutic applications. APC, antigen presenting cell; ELISA, enzyme linked immunosorbent assay; IVIG, intravenous immunoglobulin; mAb, monoclonal antibody. Passive immunity refers to, for example, protection provided by horse serum against snake venom or from viral infection with transferred mAbs. IVIG is used to provide passive immunity against pathogens in immune-deficient patients but also has anti-inflammatory activities, dependent on antibody glycosylation and binding of inhibitory receptors, and can be used to treat some inflammatory and autoimmune diseases. B cells may be engineered (e.g. using CRISPR-Cas9 based gene targeting) to secrete pre-defined antibodies or other proteins such as plasma clotting factors. As antigen presenting cells, B cells may prime T cells that have protective, autoreactive, or allergy-promoting effector functions beyond providing help to B cells. For details about other parts of the diagram, see main text.

Figure 2.. Cellular dynamics underlying a B cell response.

Circulating antigen specific B cells (blue) that are as rare as 1 in 10⁴ to 1 in 10⁶ enter and survey an antigen draining lymph node (LN). A B cell encounters an opsonized (complement coated) antigen displayed on a follicular dendritic cell (FDC) process and receives B cell receptor (BCR) and complement receptor-2 (CR2) signals. Activation involves upregulation of surface molecules, antigen internalization processing and (in the case of protein-containing antigens) presentation as MHC class II peptide (MHCIIpep) complexes, and entry into G1 of cell cycle. If the antigen engages multiple BCRs and/or coreceptors on the B cell, a T-independent (TI) proliferative response ensues. Lower valency protein-containing antigens drive T-dependent (TD) responses, where the B cell depends on signals from helper T cells to undergo proliferation. The proliferative phase is followed by differentiation into short-lived plasma cells (SLPCs), germinal center (GC) B cells, and/or memory B cells (Bmem). The relative differentiation to these distinct states varies and depends on the integration of signals received by the B cell including via the BCR, co-receptors, and T cell help. GC B cells take on a dendritic morphology that may facilitate antigen encounter and affinity discrimination. GCs give rise to more SLPCs, to memory B cells and to long-lived plasma cells (LLPCs).

Figure 3.. Class switch recombination at multiple stages.

Upon receiving appropriate activation signals, B cells undergo a DNA rearrangement of their Ig Hc gene leading to class switch recombination (CSR, also known as isotype switching). In this process, DNA encoding the constant region of the antibody is replaced with a downstream gene sequence to encode a different isotype. Naïve B cells express IgD and/or IgM, and CSR leads to the expression of IgG, IgE, or IgA isotypes. CSR may occur directly (for example, from IgM/IgD to IgE), or sequentially (for example, from IgM/IgD to IgG to IgE). Memory B cells may also undergo CSR upon re-activation (for example, from IgG to IgE). Once cells differentiate into PCs, CSR is extinguished. There are thus multiple paths giving rise to PCs expressing particular antibody isotypes. As well as secreting antibody, IgM, IgA and IgE PCs retain membrane forms of the antibody.

Figure 4.. Germinal centers (GCs) promote selectivity and diversity in foreign antigen-reactive B cells.

(A) A self-reactive B cell that has bound a cross-reactive higher valency foreign antigen undergoes somatic hypermutation in a GC, leading to the emergence of foreign antigen-selective clones. This process is referred to as ‘clonal redemption’. (B) Models to explain how multiple properties of GCs may support induction of a diversity of antigen-reactive clones. (i) Confinement of cells to individual GCs for some period of clonal evolution may help ensure distinct clones emerge (as memory cells and PCs) from the separate GCs. (ii) GCs output a diversity of clones early in the response (mostly as memory B cells) followed by more restricted clones (mostly as PCs) after longer periods of selection. (iii) Some GCs undergo clonal bursting and are taken over by one or a few clones while others in the same lymphoid tissue refrain from clonal bursting and produce a diversity of output clones over a sustained period.