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60 Part II: The Organization of the Lymphohematopoietic Tissues Chapter 5: Structure of the Marrow and the Hematopoietic Microenvironment 61

factor-L (ECFL), characterizing complex cell–cell, cell adhesion pro- or immature plasma cells. The immature plasma cells that have dif-
193
tein, stromal cell cytokine, and chemokine signals within the marrow ferentiated in the spleen and will become the long-lived plasma cells
microenvironment. return home to the marrow, where they are located in contact with
CXCL12-producing stromal cells. A negative feedback is completed as
the mature plasma cells either compete with the prepro-B cells for sites
LYMPHOCYTES on the CXCL12-producing stromal cells or directly induce apoptosis
204
Lymphocytes, including T, natural killer (NK), B, and plasma cells, of the prepro-B cells. Marrow blood vessel-associated dendritic cells
and macrophages, including monocyte-derived, antigen-presenting produce macrophage migration-inhibition factor, a cytokine required
dendritic cells, arise from the HSCs and undergo part of their differen- for survival of mature B lymphocytes that have matured in secondary
tiation in the marrow. They then circulate and, in the case of the lym- lymphoid organs and recirculated to the marrow. 195
phoid cells, reside and further differentiate in other organs such as the
thymus, spleen or lymph nodes, before returning to the marrow, where
they terminally differentiate and form part of the marrow microenvi- MACROPHAGES
ronment by producing growth factors (IL-3, CCL3) and participating Hematopoietic progenitors restricted to monocyte/macrophage differ-
in cell–cell interactions with developing progenitors. 84,101,194 Monocytic/ entiation are characterized by expression of M-CSF receptors (FMS),
macrophage progenitor cells can enter the circulation and later enter membrane-activating complex-1 (CD11b), and F4/80 antigen, and give
many different tissues where they differentiate into macrophages. In rise to monocytes that enter the blood. These nondividing monocytes
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the marrow, the monocytic/macrophage progenitors can differentiate can then enter various organs, including a subset with high Ly6C that
into macrophages or fuse and become osteoclasts. Lymphocytes and reenter the marrow where they become macrophages and antigen-pre-
macrophages concentrate around arterial vessels, near the center of senting dendritic cells. 205,206 Although they are both descendants of
the hematopoietic cords. B cells also cluster near the osteal surface. 92,93 similar M-CSF–dependent monocytic progenitors, macrophages dif-
Mature B and T lymphocytes in the marrow are in contact with a spe- fer from osteoclasts by their single nucleus and, in mice, expression
cific set of monocyte-derived, antigen-presenting dendritic cells that are of F4/80 antigen as well as lack of TRAP and calcitonin receptors.
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clustered around the blood vessels. 195 Marrow macrophage phenotype is regulated by adjoining stromal
208
Lymphocytic differentiation begins as HSCs that have committed cell–accessory cell–derived colony-stimulating factors and cytokines,
to differentiation as multipotent HPCs (MPPs) lose their potential to such as M-CSF–induced upregulation of α β - and α β -integrin expres-
5 1
4 1
become megakaryocytic-erythroid progenitors (MEPs) and granu- sion and Flt-3 ligand-promoting macrophage outgrowth with B-cell–
209
locyte-macrophage (GM) progenitors; this change in differentiation associated antigens. Macrophages are an integral component of the
210
potential is detectable as the upregulation of lymphoid-specific tran- local microenvironment and regulate hematopoiesis via a complex
scripts, that is, they are lymphoid-primed multipotent progenitors array of dual-acting stem cell stimulatory and inhibitory factors, such as
(LMPPs). The commitment of LMPPs to lymphoid differentiation in IL-1, CCL3, TNF-α, and TGF-β. 211–213 Macrophages respond to PDGF
these early-stage HPCs is reinforced by progressive expression of FMS- by upregulating IL-1 secretion and thereby activating primitive hemato-
214
like tyrosine kinase 3 (Flt-3), IL-7 receptors (IL-7R), and recombina- poietic cells. Macrophages also modulate the structure and composi-
tion activating genes-1/2 (Rag-1/2) proteins. 196,197 These early lymphoid tion of the extracellular matrix (ECM) and its FN content. 215
progenitors (ELPs) require a microenvironment provided by MSCs and Specialized macrophages termed osteomacs form a canopy over
their osteogenic progeny which supplies VCAM-1, CXCL12, Flt-3 lig- the active osteoblasts and osteoclasts on the endosteal surface, where
and, and IL-7. 198,199 The ELPs enter the blood with transit to the thymus the macrophages coordinate the bone-forming activity of osteoblasts
206
where they undergo differentiation into T cells. In addition, to its role and bone-resorbing activity of osteoclasts. Another subset of mac-
as site of early T-lymphocyte development, the marrow acts a secondary rophages, which are identified by CD169 (sialoadhesin/Siglec-1 [sialic
organ for the proliferation of mature CD8 and CD4 memory T lympho- acid-binding immunoglobulin-like lectin-1]), act to retain in the mar-
cytes. Although no specific organized structure or niche has been found row those HSCs and early progenitor cells that are capable of circula-
for these T lymphocytes, they can represent up to 4 percent of nucleated tion in the blood. CD169-expressing macrophages also comprise
216
cells in the marrow that they reenter by migrating through the sinus- the central macrophages of erythroblastic islands that interact directly
217
oidal endothelium from the blood. Alternatively, LMPPs can remain with erythroid cells, enhancing their proliferation and differentiation.
200
in the marrow and differentiate into common lymphocyte progenitors Similarly, mature B and T lymphocytes in the marrow are supported in
(CLPs) that give rise to NK progenitor cells, which differentiate in the the specific microenvironment provided by monocyte-derived, antigen-
marrow, or prepro-B cells that mature to the pro-B cells, which migrate presenting dendritic cells that are clustered around the blood vessels. 195
from the marrow to the lymph nodes or spleen where they differentiate
further. 196,197
Marrow stromal cells facilitate the maturation of NK cells, an EXTRACELLULAR MATRIX
201
effect likely mediated by stromal-derived Flt-3 ligand and IL-15. Mesenchymal cells forming the cellular stroma in the marrow create
202
Within the marrow, both NK cells and CD8+ memory T cells require a network of ECM proteins, such as proteoglycans or glycosamino-
the coordinated expression of secreted IL-15 and surface IL-15 recep- glycans (GAGs), FN, tenascin, collagen, laminin, and thrombospon-
tors by other marrow cells for their survival and development. The din (TSP). 218–221 Localizing signals are provided by stromal–ECM and
203
marrow MSCs and their osteogenic progeny also create a microenvi- hematopoietic cell adhesive interactions 222,223 in concert with chemok-
225
224
ronment for proliferation and differentiation of ELPs through the later ines and cytokines bound to heparin-like structures in the GAGs.
sequential lymphoid stages of CLPs, prepro-B cells, pro-B cells, and The binding of specific cytokines may enhance the activity of a cytokine
pre-B cells via the provision of osterix and galectin-1. 198 if the GAG-binding site does not interfere with the site that binds the
The differentiation stages subsequent to the pro-B cells occur after cytokine receptor, whereas GAG-binding sites that overlap or interfere
the cells enter the blood and seed the lymphoid follicles of the sec- with a cytokine receptor-binding site can inhibit the cytokine func-
ondary lymphoid organs, mainly spleen and lymph nodes. From these tion. Table 5–1 lists the cytokines that are presented on the surface of
225
lymphoid organs, the cells then reenter the blood as B lymphocytes stromal cells and matrix-binding chemokines and cytokines. 225–238

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