B cells in the periphery are made up of distinct subsets that develop from different progenitors (Fig. 1). Bone marrow derived HSCs give rise to the majority of B cells. These cells, also called B-2 cells, rapidly pass through two transitional stages and can commit to development either into follicular B cells or into marginal-zone B cells. Follicular B cells are also often called recirculating B cells because they migrate via the blood from one secondary lymphoid organ to another, and within these organs they reside in follicles. B-1 cells represent a distinct lineage that develops from fetal liver–derived HSCs.
Fig1. B-lymphocyte subsets. (A) Most B cells that develop from fetal liver (FL)–derived stem cells differentiate into the B-1 lineage. (B) B lymphocytes that arise from bone marrow (BM) precursors after birth give rise to the B-2 lineage. Two major subsets of B lymphocytes are derived from B-2 B-cell precursors. Follicular B cells are recirculating lymphocytes; marginal-zone B cells are abundant in the spleen in rodents, but can also be found in lymph nodes in humans. CD21 is expressed on both follicular and marginal-zone B cells, but the levels of this coreceptor are higher on marginal-zone B cells. HSC, Hematopoietic stem cell; Ig, immunoglobulin.
Follicular B Cells. Most mature B cells belong to the follicular B-cell subset and are capable of recognizing and responding to antigens. Each of these B cells coexpresses membrane-associated IgM and IgD in which the µ and δ Ig heavy chains use the same VDJ exon to generate the V domain. In each B cell, these heavy chain proteins associate with the same κ or λ light chain to produce two membrane receptors with the same antigen specificity. Each B cell produces a long primary RNA transcript containing the rear ranged VDJ unit that encodes the V domain, as well as both the Cµ and Cδ genes (Fig. 2). If the primary transcript is cleaved and polyadenylated after the µ exons, after RNA splicing the VDJ exon becomes contiguous with Cµ exons, resulting in the generation of a µ mRNA. If, however, the VDJ complex is not linked to Cµ exons but is spliced to Cδ exons, a δ mRNA is produced. Subsequent translation results in the synthesis of a complete µ or δ heavy-chain protein, both containing the same V region and therefore the same specificity. The precise mechanisms that regulate the choice of polyadenylation or splice acceptor sites, by which the rearranged VDJ is joined to either Cµ or Cδ, are poorly understood. The signals that determine when and why a B cell expresses both IgM and IgD rather than IgM alone are also not known.
Fig2. Coexpression of immunoglobulin M (IgM) and IgD. Alternative processing of a primary RNA transcript results in the formation of a µ or δ mRNA. Dashed lines indicate the H chain segments that are joined by RNA splicing. C, Constant; D, diversity; J, joining; L, leader; V, variable.
The coexpression of IgM and IgD on follicular B cells is accompanied by the acquisition of functional competence, and this is why IgM+IgD+ B cells are also called mature B cells. This correlation between expression of IgD and acquisition of functional competence has led to the suggestion that IgD is the essential activating receptor of mature B cells. However, there is no evidence for a functional difference between membrane IgM and membrane IgD. Moreover, knockout of the Ig δ gene in mice does not have a significant impact on the maturation or antigen-induced responses of B cells.
Naive follicular B cells survive for limited periods until they encounter antigens (see Chapter 2). Follicular B-cell survival depends on tonic antigen-independent signals from the BCR as well as stimulation by a cytokine of the TNF family called BAFF (B cell–activating factor, also known as BLyS, for B-lymphocyte stimulator), which provides maturation and survival signals through the BAFF receptor. BAFF and a related ligand, APRIL, can bind to two other receptors, TACI and BCMA, which participate in later stages of B-cell activation and differentiation. These cytokines are produced by specialized fibroblastic reticular cells and by myeloid cells in lymphoid follicles and in the bone marrow. Naive follicular B cells, like recirculating naive T cells, leave lymph nodes through efferent lymphatics, enter the blood, and return to lymph nodes via high endothelial venules.
Mature, naive B cells are responsive to antigens, and unless the cells encounter antigens that they recognize with high affinity and respond to, they die in a few months.
B-1 and Marginal Zone B Cells. A subset of B lymphocytes, called B-1 cells, expresses antigen receptors with limited diversity and may serve roles in humoral immunity that are different from those of follicular B cells. B-1 cells develop from fetal liver–derived HSCs and are best defined in rodents. Most murine B-1 cells express the CD5 molecule. After birth, large numbers of these cells are found as a self-renewing population in the peritoneum and mucosal sites. They develop earlier during ontogeny than follicular and marginal zone B cells, express a relatively limited repertoire of V genes, and exhibit far less junctional diversity than conventional B cells (because TdT is not expressed in developing B-1 cells in the fetal liver). B-1 cells spontaneously secrete IgM antibodies that often react with microbial polysaccharides and lipids as well as oxidized lipids produced by lipid peroxidation. These antibodies are sometimes called natural antibodies because they are present in individuals without overt immunization, although it is possible that microbial flora in the gut are the source of antigens that stimulate their production. B-1 cells contribute to rapid antibody production against microbes in particular tissues, such as the peritoneum. At mucosal sites, as many as half the IgA-secreting plasma cells in the lamina propria may be derived from B-1 cells. B-1 cells are analogous to γδ T cells in that they both have antigen receptor repertoires of limited diversity and they are both presumed to respond to antigens that are commonly encountered at epithelial interfaces with the external environment. B-1 cells in humans are abundant in cord blood and in the circulation in young children but in adults very few B-1 cells are observed in the circulation. There remain some unresolved issues about human B-1 cells. While it is possible that in adults these cells reside mainly in serosal cavities and mucosal sites (as is the case in adult mice), detailed studies on human tissues to establish this are awaited. Also, while humans do express natural IgM antibodies against microbes and blood group antigens, it is unclear whether these originate from B-1 cells or marginal zone B cells or both.
Marginal zone B cells are located primarily in the vicinity of the marginal sinus in the spleen and, like B-1 cells, have limited diversity, respond to polysaccharide antigens, and produce natural antibodies. Marginal zone B cells exist in both mice and humans and express IgM in the absence of IgD and additional surface receptors that distinguish them from follicular B cells. In rodents, marginal-zone B cells are present only in the spleen and require NOTCH signaling for their development. In humans, cells that are commonly called marginal zone B cells express IgM and CD27, are heterogeneous, and are found in the spleen as well as outside follicular areas near the periphery of lymph nodes and in the circulation. These human marginal zone B cells exist as two distinguishable subsets. MZB1 cells, which correspond to rodent IgM memory B cells, have higher somatic hypermutation levels of Ig genes and do not express genes that are induced by NOTCH signaling. MZB2 cells are the human counterparts of rodent marginal zone B cells, are more “naïve-like,” have lower levels of somatic hypermutation than MZB1 cells, develop in a NOTCH dependent manner, and express genes induced by NOTCH signaling. MZB2 cells in humans respond rapidly to blood-borne microbes and differentiate into short-lived IgM-secreting plasma cells, but can also participate in T-dependent responses. These B cells, as well as their rodent counterparts, express high levels of CD1c (an HLA class I–like molecule of the CD1 family that is specialized for presentation of lipid antigens to NKT cells). Thus, MZB2 cells can collaborate with NKT cells to receive T-cell help and secrete antibodies in response to lipid antigens.
