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CHaPTEr 7 B-Cell Development and Differentiation 113

cytokine, IL-1, can also act as a dose-dependent positive or cell–activating factor (BAFF) of the tumor necrosis factor (TNF)
negative modulator of B lymphopoiesis. family, with its receptor, BAFF-R, which is expressed primarily
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Systemic hormones also regulate lymphopoiesis. A role for sex on B cells. Death signals triggered through interaction of the
steroids is suggested by the reduction in preB cells during pregnancy. BCR with self antigen can be counterbalanced by stimulation
Estradiol can also alter later stages of B-cell development, promoting of BAFF-R, which enhances expression of survival factors, such
expansion of the marginal zone (MZ) compartment. Prolactin as Bcl-2, and at the same time downregulates proapoptotic factors.
appears to enhance production of both MZ and follicular B cells. BAFF and a second TNF family member APRIL (a proliferation-
Mice with a LOF mutation in the Pit-1 transcription factor gene inducing ligand) are essential factors for B-cell development and
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do not produce growth hormone, prolactin, or thyroid-stimulating also for their long-term maintenance. With the development
hormone. These dwarf mice exhibit a defect in B-cell development of plasma cells, BAFF-R is downregulated while the receptors
that is correctable by the thyroid hormone thyroxine. 16 transmembrane activator and calcium-modulator and cyclophilin
ligand (CAML) interactor (TACI) and B-cell maturation antigen
KEY CONCEPTS (BCMA) are upregulated. In contrast to BAFF-R, these members
of the TNF-R family can bind both BAFF and APRIL. APRIL
B-Cell Development in the Periphery can induce isotype switching in naïve human B cells. More
importantly, it is a crucial survival factor supporting the longevity
• T cell–independent activation of naïve B cells results in terminal dif-
ferentiation into short-lived plasma cells. of plasma cells.
• T cell–dependent activation of B cells:
• Induces germinal center formation, permitting somatic hypermutation B CELLS AND THE RESPONSE TO ANTIGEN
and class-switch recombination (CSR)
• Results in differentiation into high-affinity memory B cells (reactive T Cell–Independent Antigens
memory) and plasma cells secreting high-affinity antibodies (protec- Unlike T cells, which require presentation of antigen by other
tive memory)
• Generates long-term humoral immune protection cells, B cells can respond directly to an antigen as long as antigen
• The longevity of plasma cells is supported by highly specialized survival is able to cross-link the BCR. Such antigens, especially those
niches in bone marrow. that by nature cannot be recognized by T cells (e.g., DNA or
• T-follicular helper (Tfh) cells control late B-cell differentiation by cell- polysaccharides), can induce a B-cell response independent of
bound ligands and secreted cytokines. T-cell help. Depending on the cytokine milieu, B cells may even
• Activated B cells control T-cell development by presentation of antigen class switch (Chapter 4; and see below), although the range of
and costimulation.
available classes appears to be restricted. B cells that are activated
by antigen alone do not take part in a germinal center (GC)
B-CELL DEVELOPMENT IN THE PERIPHERY reaction (see below).
The life span of mature B cells expressing surface IgM and IgD T Cell–Dependent Antigens
appears entirely dependent on antigen selection. After leaving Activated B cells express both MHC class I and class II molecules
bone marrow, unstimulated cells live for only a few days. Deletion on their cell surface (Chapter 5). They can thus present both
of the transmembrane/intracellular domains of the BCR leads intracellular and extracellular antigens to CD4 T-helper (Th) and
to loss of mature B cells, which indicates that signaling through CD8 T cytotoxic lymphocytes (Chapter 6). Their role as antigen-
the BCR is essential for their survival. As originally postulated presenting cells (APCs) is enhanced when they present peptides
by Burnet’s “clonal selection” theory, B cells are rescued from from the same antigen they have taken up with their antibodies.
apoptosis by their response to a cognate antigen. The reaction Cognate recognition of the same antigen by both a B cell and a
to antigen leads to activation, which can then be followed by T cell permits each of these cells to reciprocally activate the other.
diversification. T cell–activated B cells express the costimulatory molecules
The nature of the activation process is critical. T cell– CD80 and CD86. These cell-surface molecules are required for
independent stimulation of B cells induces differentiation into activation of T cells via CD28, and for inactivation by CD152
short-lived plasma cells with limited class switching. T-dependent (cytotoxic T-lymphocyte antigen-4 [CTLA-4]). Since B cells do
stimulation adds additional layers of diversification, including not express IL-12, they do not induce expression of IFN-γ in
SHM of the variable domains, which permits affinity maturation, the activated T cells but rather favor the differentiation of activated
class switching to the entire array of classes available (Chapter T cells into IL-4, -5, -10, and - 13 expressing Th2 cells and IL-21
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4), and differentiation into the long-lived memory B-cell pool secreting T-follicular helper (Tfh) cells. These cytokines can
or into the long-lived plasma-cell population. support the CD40-induced expansion of memory B cells (IL-4),
CD40-induced class-switch recombination (CSR) to IgG4 or
BAFF and APRIL Can Play Key Roles in the Development IgE (IL-4), and differentiation of antigen-activated B cells into
of Mature B Cells high-affinity plasma cells (IL-21).
B cells leave bone marrow while still undergoing initial matura-
tion, demonstrating progressively higher levels of IgD expression ORGANIZATION OF PERIPHERAL
with a commensurate lowering of IgM. The splenic environment LYMPHOID TISSUES
plays a key role in this maturation process. Immigrant splenic
maturing B cells pass through two transitional stages, known as B lymphocytes enter the secondary lymphoid organs through
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transitional stages 1 (T1) and 2 (T2). Only a minority of these defined ways. Each organ exhibits a preferred route of entry. For
cells successfully make the transition, as this differentiation step example, most lymphocytes enter the spleen through the blood-
is a crucial checkpoint for controlling self-reactivity. Passage stream, whereas lymphocytes enter lymph nodes and the Peyer
through this checkpoint requires the interaction of soluble B patches through high endothelial venules. DCs, macrophages,