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92 Part II: The Organization of the Lymphohematopoietic Tissues Chapter 6: The Organization and Structure of Lymphoid Tissues 93

activated, typically forming blasts that have abundant cytoplasm and is mediated by the TCR for antigen. Which T cells are activated is deter-
round, cleaved, or convoluted shapes. Follicular dendritic cells also are mined by the specificity of the TCRs, the structure of MHC molecules,
found within the germinal centers. These cells can trap and retain anti- and the nature of antigen-presenting cells, including the dendritic retic-
gens for months, possibly in the form of immune complexes. The ger- ular cells, macrophages, and B cells.
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minal centers of the secondary follicle may gradually regress after the Along with TCR recognition of processed antigen presented in the
antigenic stimulus is eliminated. MHC of the antigen-presenting cell, adequate T-cell activation requires
Surrounding the lymphoid follicles of the superficial cortex are secondary signals, or costimulation, delivered through accessory mol-
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sheets of lymphocytes that extend to the deep cortex, the paracortex, ecules, such as CD28. Without these secondary signals, T cells may
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that blend into medullary cords of cells. The paracortical zones are become anergic or specifically nonresponsive to antigen stimulation.
formed mostly of T cells. The ratio of T cells to B cells in these zones This specific suppression is thought to play an important regulatory role
is approximately 3:1. The medulla, however, contains scattered B cells, in the maintenance of self-tolerance. 72,73
dendritic cells, macrophages, rare NK cells, and, during an immune T-cell recognition of specific antigen may induce release of soluble
response, plasma cells. The superficial cortex and medulla of the lymph factors, such as interleukins, that can activate the T cells themselves or
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nodes are the thymic-independent areas, while the deep cortex is partic- have paracrine effects on other neighboring leukocytes. Also, activated
ularly enriched with T cells, forming an area that sometimes is referred T cells express surface molecules, such as CD40-ligand (CD154), that
to as the thymic-dependent area. The major T-cell population found also can activate B cells, dendritic cells, or macrophages. 75,76
within the lymph node consists of CD4+ T cells. The scattering of CD4+ The T-dependent immune response includes the formation of
T cells in the follicles, and in more prominent numbers in the interfol- early germinal centers within days after antigen exposure. There is a
licular zones, reveals the proximity of CD4+ T and B cells important mixture of B cells and activated CD4+ T cells in the lymphoid folli-
for T-B cooperation during proliferation and maturation of antigen- cles. T-B cooperation involves the accessory B-cell antigen CD40 and
stimulated B cells. 58 the CD154 antigen expressed on activated T cells (Chap. 76). Activated
The T-cell–rich paracortex is also relatively enriched with special- B cells differentiate and take on the cytomorphologic characteristics of
ized NK cells and other innate lymphoid cell (ILC) populations that centroblasts and comprise the largest numbers of cells in the early ger-
likely have roles in shaping innate and adaptive immune responses minal center. Subsequently, centroblasts give rise to smaller B cells,
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in lymph nodes, as well as other secondary lymphoid tissues (SLT), the centrocytes. B cells undergo affinity maturation within the germi-
through the production of immunomodulatory cytokines. The NK cell nal center. During this process, the genes encoding the surface immu-
population present in the lymph node paracortex is predominantly noglobulin of B cells undergo high rates of mutation, called somatic
composed of the CD56 bright subset that can rapidly produce cytokines, hypermutation. 53,77 B cells that express immunoglobulin with little or
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such as interferon-γ and tumor necrosis factor-α, in response to mono- no affinity for antigen undergo apoptosis. The resulting cellular debris
cyte-derived cytokines (IL-12, IL-15, and IL-18). 59,60 However, these NK is tingible, or capable of being stained, and is found prominently within
dim
cells show relatively weak cytotoxicity in comparison to CD56 NK macrophages specifically designated tingible body macrophages. On the
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cells that predominate in the blood (Chap. 77). There is accumulating other hand, B cells expressing surface immunoglobulin with high affin-
evidence that CD56 bright NK cells represent the immediate precursors to ity for antigen are selected to proliferate and differentiate to memory B
dim
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CD56 NK cells and likely differentiate into the latter just prior to their cells or plasma cells. As well as promoting activation of B cells, CD4+
egress from lymph nodes. 62–64 Moreover, CD34+CD45RA+ hematopoi- T cells, and CD8+ T cells may give rise to circulating memory T cells. 79,80
etic progenitor cells capable of giving rise to CD56 bright NK cells are also Following the release of specific antibody, antigen–antibody com-
enriched in the lymph node paracortex indicating that these tissues are plexes may form and become sequestered on the surface of follicular
also likely sites of NK cell development. 65–67 dendritic cells within the germinal centers. These antigen–antibody
Lymphocytes primarily enter lymphatic tissues from the blood by complexes produce a coating of small, bead-like, immune complex-
migrating across the tall, active endothelium of specialized postcapil- coated bodies called iccosomes. Iccosomes may be presented to CD4+
lary venules called high endothelial venules. Cellular adhesion mole- T cells by B cells and dendritic cells. Iccosomes also appear to assist
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cules and various chemokines, including CXCL13, CCL19, and CCL21, in anamnestic recall following reentry of antigen in the host. T- and
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are responsible for the pattern of lymphocyte trafficking and determine B-cell memory functions depend upon persistence of antigen. 82
the associations among stromal (e.g., reticular and endothelial) and par-
enchymal (e.g., T and B lymphocytes, dendritic cells, and macrophages)
cells in the lymphoid tissues. 54,69 PERIPHERAL LYMPHOID TISSUES
MUCOSA-ASSOCIATED LYMPHOID TISSUES
LYMPH NODE FUNCTION The mucosa-associated lymphoid tissues (MALTs) are diffusely orga-
The lymph node is the site where different types of lymphocytes, macro- nized aggregates of lymphocytes that protect the respiratory and gas-
phages, and dendritic cells can interact with one another to generate an trointestinal epithelium. The lymphoid aggregates associated with
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immune response to antigens carried within the lymph. As the lymph the respiratory epithelium are sometimes referred to as the bronchi-
passes across the nodes from afferent to efferent lymphatic vessels, par- al-associated lymphoid tissue. The lymphoid aggregates associated with
ticulate antigens are removed by the phagocytic cells and transported the intestinal epithelium are sometimes referred to as the gut-associ-
into the lymphoid tissue of the lymph node. Abnormal cells within the ated lymphoid tissue (GALT). Lymphocytes in the GALT are located
1
lymph, such as neoplastic cells, also can be trapped within the lymph in three main regions: within the epithelial layer, scattered through the
node. lamina propria, and clustered in organized collections in the lamina
Within the lymph node, antigen is presented to T cells as processed propria. The latter includes the tonsils, adenoids, appendix, and spe-
peptides by MHC molecules of antigen-presenting cells (Chap. 76). cialized structures called Peyer patches found in the ileum (Fig. 6–9).
Various T-cell subsets comprise a network of interactive cells. CD4+ Most intraepithelial lymphocytes are CD8+ T cells, 10 percent of which
and CD8+ cell-mediated contacts, as well as T-cell–derived soluble express the γ/δ form of the TCR (Chap. 76). On the other hand, the
factors, induce and regulate the immune response. T-cell recognition intestinal lamina propria contains a mixed population of cells, including

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