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Chapter 20 B-Cell Development 217

cell adhesion molecule-1 (VCAM-1). VLA-4 also promotes binding pituitary–thyroid axis because mice deficient in the production of
to fibronectin, an extracellular matrix protein. CD44 on developing B thyroid hormone or expression of the thyroid hormone receptor
lineage cells has been implicated in mediating stromal cell–lymphocyte exhibit suppressed BM B lymphopoiesis. Whether or not these events
interactions in the mouse through binding to stromal cell–derived also occur in human B lymphopoiesis has not been established. It also
hyaluronate. These intercellular interactions presumably would allow has been demonstrated that hormones can negatively affect B-cell
B cells to receive proliferative or developmental signals (or both) development. In particular, increased levels of estrogens occurring
from stromal cells. The stromal cells may not be passive populations during pregnancy inhibit lymphopoiesis.
that constitutively provide these signals. Instead, the binding of the
B-lineage cell may stimulate the stromal cell in turn to produce such
differentiation or growth-potentiating activities. Various cytokines that FETAL B-CELL DEVELOPMENT
regulate the growth, differentiation, and/or survival of B lineage cells
have also been described and include C-X-C motif chemokine ligand Most knowledge of fetal hematopoiesis is based on studies in mice.
12 (CXCL12; SDF1), Flt3 ligand, stem cell factor, IL-7, Wnt family It has long been recognized that some blood cells in that species
members, transforming growth factor beta (TGF-β) family members, are generated prior to the appearance of HSCs in an early wave
and thymic stromal lymphopoietin (TSLP). 17 of hematopoiesis that occurs in tissues such as the yolk sac. It has
A full discussion of these and additional factors that regulate B-cell traditionally been thought that this pre-HSC wave of development is
development is beyond the scope of this chapter. However, the focus restricted to the production of erythroid and selected myeloid cells.
can be narrowed considerably when only those with obligate effects However, emerging data suggest that B- and T-cell potential is also
on B-cell development are considered. In this regard, the critical B associated with this early wave of hematopoiesis. 20,21 The contribution
lymphopoietic cytokine in mice is IL-7, which binds to the IL-7 of B cells generated in this pre-HSC phase to the adult immune
receptor (IL-7R). The IL-7R is formed by the IL-7 receptor α chain system remains to be determined. HSCs are generated at embryonic
and the common cytokine γ chain. The Janus kinases (JAKs) JAK3 day 10.5 of murine gestation, and their B lineage progeny can be
and JAK1 are associated with the γc and IL–7Rα, respectively, and are detected several days thereafter in fetal liver, BM, and spleen.
critical for IL-7 receptor-mediated signaling. When IL-7 binds to the Studies of human fetal B-cell development are limited. Hemato-
IL-7 receptor, these JAKs are phosphorylated, and this in turn recruits poiesis initiates in the human yolk sac at 3 weeks of gestation, pre-B
signal transducer and activator of transcription 5A (STAT5A) and cells are present in human fetal liver by week 8 of gestation, and
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STAT5B. The STAT molecules can then translocate to the nucleus surface IgM cells are detectable at week 9. IgM-expressing cells have
where they act as transcriptional activators. In addition to stimulating also been observed in additional human fetal tissues that include the
the growth and survival of developing B lineage cells, IL-7 signaling omentum, the peritoneal cavity, and the spleen.
also potentiates the recombination of a VH region gene segment to
an already rearranged DJH complex. The requirement for IL-7 in
murine B-cell development is demonstrated by studies showing a B-1 B Cells in Mice
block in B-cell development at approximately the pro-B-cell stage in
IL-7 and IL-7 receptor knock-out mice. 14 The B cells that are produced in adult BM and that constitute the
Developing B-cell progenitors are exposed to IL-7 and other majority of B cells in the spleen and lymph nodes are often referred to
signals, and this is thought to occur as they traffic through different as B-2 B cells. This nomenclature serves to contrast them with another
niches in the BM (Fig. 20.4). The most immature B-cell progenitors functionally distinct population of mature B cells that are referred to
express the CXC-chemokine receptor 4 (CXCR4) receptor and asso- as B-1 B cells. B-1 B cells are best characterized in mice, where they
ciate with stromal cells that express high levels of its ligand, CXCL12. constitute around 5% of total B lymphocytes. Murine B-1 B cells
CXCL12 induces focal adhesion kinase (FAK) phosphorylation in preferentially localize in serous cavities and can be distinguished by
pro-B cells, and this in turn is thought to promote VLA-4-mediated their unusual phenotype that includes high levels of sIgM, low levels
adhesion to VCAM-1 expressing stroma. As maturation occurs, pro-B of sIgD, and CD11b, a determinant expressed on myeloid cells. B-1
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cells migrate towards IL-7-producing stromal cells. Ultimately, pre-B B cells can be further subdivided into B-1a B cells that are CD5
cells dissociate from the IL-7-rich environment. As discussed earlier, and B-1b B cells that do not express this determinant. Antibodies
this movement away from IL-7-expressing niches may be associated from B-1 B cells, at least in mice, are required for protection against
with their reduced proliferation, induction of Rag gene expression, pathogens such as Streptococcus pneumoniae.
and Ig light chain recombination. Finally, newly produced B cells B-1 B cells are generated most efficiently from precursors that
exit the BM. 18 arise in the fetus. Thus, although HSCs from fetal liver can efficiently
generate both B-1 and B-2 B cells, those from the adult primarily
produce B-2 B lymphocytes. These observations support the long-
IL-7 in Humans held view that B-1 cells are a distinct B-cell lineage preferentially
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derived from fetal precursors. The description of a phenotypically
The precise role of IL-7 during human B-cell development is identifiable B-1 B-cell–specified progenitor that is preferentially
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unclear. Human CD34 CD19 pro-B cells proliferate in response to generated in the fetus provided strong support for this view.
IL-7, but human B lymphopoiesis may not be dependent on IL-7, The regulation of B-1 and B-2 development is distinct, providing
because B cells are present in patients whose B lineage cells express further support for the conclusion that these are distinct B-cell popu-
a mutated IL-7Rα chain. In addition, B cells are present in patients lations. For example, although B-2 B-cell development is blocked in
with X-linked severe combined immunodeficiency; these individuals IL-7-deficient mice, B-1 development can occur. More recently, the
have mutations in the gene encoding the cytokine common γ chain, preferential generation of B-1 B cells from fetal progenitors has been
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which is part of the receptor for IL-7. Other receptors that could linked to the expression of the Lin28b miRNA binding factor by
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compensate for the loss of IL-7 receptor signaling have not been fetal HSCs and B lineage progenitors. Adult HSCs are Lin28b , but
identified. ectopic Lin28b expression in adult hematopoietic stem/progenitor
cells results in their ability to generate B-1 B cells, and B-1a B cells
in particular. 23
Systemic Factors
In addition to regulation by microenvironmental factors, there is a B-1 B Cells in Humans
growing appreciation that systemic factors, and those of endocrine
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origin in particular, also regulate B-cell development. For example, B-1a B cells in mice are CD5 , and many studies have claimed to
B-cell development in mice is dependent on the integrity of the have identified human B-1 cells based on simultaneous expression of