Secondary Lymphoid Organs: Where the Immune Response Is Initiated

As described above, lymphocytes and myeloid cells develop to maturity in the primary lymphoid system: T lymphocytes in the thymus, and B cells, monocytes, dendritic cells, and granulocytes in the bone marrow. However, they encounter antigen and initiate an immune response in the microenvironments of secondary lymphoid organs and tissues.

Secondary Lymphoid Organs Are Distributed throughout the Body and Share Some Anatomical Features

Lymph nodes and the spleen are the most highly organized of the secondary lymphoid organs and are compartmentalized from the rest of the body by a fibrous capsule. Less organized secondary lymphoid tissues are associated with the linings of multiple organ systems, including the skin and the reproductive, respiratory, and gastrointestinal tracts, all of which protect us against external pathogens. These are collectively referred to as barrier tissues.

Although secondary lymphoid tissues vary in location and degree of organization, they share key features. All secondary lymphoid structures contain anatomically distinct regions of T-cell and B-cell activity. They also generate lymphoid follicles, highly organized microenvironments responsible for the development and selection of B cells that produce high-affinity antibodies.

Key Concept:

• The immune response to antigen is initiated and organized in secondary lymphoid organs, which include the highly organized lymph nodes and spleen, as well as more loosely organized sites distributed throughout our barrier tissues, including the skin and mucosal membranes.

Blood and Lymphatics Connect Lymphoid Organs and Infected Tissue

Immune cells are highly mobile and use two different systems to traffic through tissues: the blood and lymphatic systems (Figure 2-12). Blood vessels have access to virtually every organ and tissue and are lined by endothelial cells that are very responsive to inflammatory signals. Both red and white blood cells transit through the blood—flowing away from the heart via active pumping networks (arteries) and back to the heart via passive valve-based systems (veins)—within minutes. Arteries have thick muscular walls and depend on the beating of the heart to propel cells through vessels. Veins have thinner walls and rely on a combination of internal valves and the activity of muscles to return cells to the heart.

FIGURE 2-12 The human lymphatic system. The primary organs (bone marrow and thymus) are shown in red; secondary organs and tissues, in blue. These structurally and functionally diverse lymphoid organs and tissues are interconnected by the blood vessels (not shown) and lymphatic vessels (purple). Most of the body’s lymphatics eventually drain into the thoracic duct, which empties into the left subclavian vein. The vessels draining the right arm and right side of the head (shaded blue) converge to form the right lymphatic duct, which empties into the right subclavian vein. Part (b) shows the lymphatic vessels in more detail, and (c) shows the relationship between blood and lymphatic capillaries in tissue. The lymphatic capillaries pick up interstitial fluid, particulate and soluble proteins, and immune cells from the tissue surrounding the blood capillaries (see arrows).

Section a shows an outline of the human body with the lymphatic system exposed. The various parts labeled on the body are tonsils, left subclavian vein, lymph nodes in the arm pit, spleen, Peyer’s patches, bone marrow, tissue lymphatics, thoracic duct, thymus, right subclavian vein, right lymphatic duct. One arrow is shown pointing from the hand toward the elbow and another arrow is shown pointing from the tissue lymphatics in the lower leg to the upper part of the body. An arrow points from the lower part of the body to the next section that shows a zoomed out image of the pelvic region. Section b shows lymph nodes and lymphatic vessel in the pelvic region. A part of the lymphatic vessel is marked and zoomed out in the next section.

Section c shows a close view of the lymph vessels and blood vessels. The parts labeled are lymphatic capillary, interstitial fluid, lymphatic vessel, venule, blood capillaries, smooth muscle, and arteriole. The lymphatic vessels and blood vessels are found close to each other. Arrows show movement of interstitial fluid from the surroundings to the lymph vessels, and movement of particulate and soluble proteins and immune cells from the blood vessels to the lymph vessels.

Endothelial cells cooperate with innate immune cells to recruit circulating white blood cells to infected tissue. These cells leave the blood by squeezing between endothelial cells and follow chemokine gradients to the site of infection (see Chapter 14).

Only white blood cells have access to the lymphatic system, a network of vessels filled with a protein-rich fluid (lymph) derived from the fluid component of blood (plasma). These vessels serve, or drain, many tissues and provide a route for activated immune cells and antigen to travel from sites of infection to secondary lymphoid organs, where they encounter and activate lymphocytes. Most secondary lymphoid tissues are, in fact, situated along the vessels of the lymphatic system. The spleen is an exception and appears to be served primarily by blood vessels.

Lymphatic vessels also return fluid that seeps from blood capillaries back to the circulatory system (see Figure 2-12c). Depending on the size and activity of an adult, seepage can generate 2.9 liters or more during a 24-hour period. This interstitial fluid permeates all tissues and bathes all cells. If this fluid were not returned to the circulation, tissues would swell, resulting in edema (specifically called lymphedema) that could become life-threatening. Some individuals are genetically predisposed to lymphedema and others experience it as a result of damage to lymphatic vessels by surgery or trauma.

The walls of the primary lymphatic vessels are thinner than those of blood vessels and more porous. They consist of a single layer of loosely apposed endothelial cells and allow fluids and cells to enter the lymphatic network relatively easily. Within these vessels, the fluid, now called lymph, flows into a series of progressively larger collecting vessels called lymphatic vessels.

All cells and fluid circulating in the lymph are ultimately returned to the blood system. The largest lymphatic vessel in our bodies, the thoracic duct, empties into the left subclavian vein. It collects lymph from all the body except the right arm and right side of the head. Lymph from these areas is collected into the right lymphatic duct, which drains into the right subclavian vein (Figure 2-12a). By returning fluid lost from the blood, the lymphatic system ensures steady-state levels of fluid within the circulatory system.

Like veins, lymphatic vessels rely on a series of one-way valves and the activity of surrounding muscles to establish a slow, low-pressure flow of lymph and cells. Therefore, activity enhances not just venous return, but lymph circulation.

All immune cells that traffic through lymph, blood, and tissues are guided by small molecules known as chemokines (see Chapter 3 and Appendix II). Chemokines are chemoattractants secreted by many different cell types including epithelial cells, stromal cells, antigen-presenting cells, lymphocytes, and granulocytes. Chemokine gradients are sensed by immune cells, which express an equally diverse set of chemokine receptors and migrate toward the source of chemokine production.

Key Concepts:

• Both blood and lymphatic vessels carry cells through and between tissues. Red and white blood cells travel from the heart in arteries and return via veins. Some white blood cells and fluid leave the blood to enter tissues. They can be picked up by the lymphatic system, which flows in one direction and ultimately connects back to the bloodstream via the thoracic duct.
• The lymphatic system also transports immune cells and foreign antigens from sites of infection to secondary lymphoid tissues and organs, where the adaptive immune response is activated.

The Lymph Node Is a Highly Specialized Secondary Lymphoid Organ

Lymph nodes (Figure 2-13) are the most specialized secondary lymphoid organs. Unlike the spleen, which also regulates red blood cell flow and fate, lymph nodes are fully committed to regulating an immune response. They are encapsulated, bean-shaped structures that include networks of stromal cells (i.e., support tissue) packed with lymphocytes, macrophages, and dendritic cells. Connected to both blood vessels and lymphatic vessels, lymph nodes are the first organized lymphoid structure to encounter antigens that enter the tissue spaces. The lymph node provides ideal microenvironments for encounters between antigen and lymphocytes and productive, organized cellular and humoral immune responses.

FIGURE 2-13 Structure of a lymph node. The microenvironments of the lymph node support distinct cell activities. (a) A drawing of the major features of a lymph node shows the major vessels that serve the organ: incoming (afferent) and outgoing (efferent) lymphatic vessels, and the arteries and veins. It also depicts the three major tissue layers: the cortex, the paracortex, and the innermost region, the medulla. Macrophages and dendritic cells, which trap antigen, are present in the cortex and paracortex. T cells are concentrated in the paracortex; B cells are primarily in the cortex, within follicles and germinal centers. The medulla is populated largely by antibody-producing plasma cells and is the site where cells exit via the efferent lymphatics. Naïve lymphocytes circulating in the blood enter the lymph node via high endothelial venules (HEVs), in a process called extravasation (see Chapter 14). Antigen and some leukocytes, including antigen-presenting cells (APCs), enter via afferent lymphatic vessels. All cells exit via efferent lymphatic vessels. (b) This stained lymph node section shows the cortex with a number of ovoid follicles, surrounding the T cell–rich paracortex. (c) Another stained lymph node section at higher magnification, showing the T-cell zone and a B-cell follicle that includes a germinal center (also referred to as a secondary follicle).

Section a shows a drawing of a lymph node, which is kidney shaped. The outer region is labeled cortex and the inner region is labeled medulla. The cortex region has a Follicle (B-cell zone) interspaced with Subcapsular sinus. The region between the cortex and medulla is labeled Paracortex (T-cell zone). Antigens and A P Cs enter the node through the incoming (afferent) lymphatics and Lymphocytes and A P Cs leave the node through the Outgoing (efferent) lymphatics. Blood vessels (arterioles and venules) are shown entering the lymph node. Naïve lymphocytes travel into the node through the blood vessels. A zoomed out image shows a cross-sectional view of the high endothelial venule (H E V). The outer layer of Blood endothelial cells are labeled.

Section b shows a stained lymph node section of the cortex region. B-cell follicle and T-cell zone: paracortex region are labeled. The next section shows a higher magnification image of the B cell follicle. The germinal center is labeled in the follicle. The surrounding T-cell zone: paracortex region is also labeled.

Structurally, a lymph node can be divided into three roughly concentric regions: the cortex, the paracortex, and the medulla, each of which supports a distinct microenvironment (see Figure 2-13a). The outermost layer, the cortex, contains lymphocytes (mostly B cells), macrophages, and follicular dendritic cells arranged in follicles. Beneath the cortex is the paracortex, which is populated largely by T lymphocytes but also contains dendritic cells that have migrated into the lymph node from the surrounding tissues (Figure 2-13b and c). The medulla is the innermost layer and the site where lymphocytes exit (egress) the lymph node through the outgoing (efferent) lymphatics. It is more sparsely populated with lymphoid lineage cells, which include plasma cells that are actively secreting antibody molecules.

Antigen travels from infected tissue to the cortex of the lymph node via the incoming (afferent) lymphatic vessels, which pierce the capsule of a lymph node at numerous sites and empty lymph into the subcapsular sinus (see Figure 2-13a). It enters either in particulate form or is processed and presented as peptides on the surface of migrating antigen-presenting cells. Particulate antigen can be trapped by resident antigen-presenting cells in the subcapsular sinus or cortex, where it is passed to other antigen-presenting cells, including B lymphocytes in the follicles. Alternatively, particulate antigen can be processed and presented as peptide-MHC complexes on cell surfaces of resident dendritic cells that are already in the T cell–rich paracortex.

T Cells in the Lymph Node

It takes every naïve T lymphocyte about 16 to 24 hours to browse the MHC-peptide combinations presented by the antigen-presenting cells (APCs) in a single lymph node. Naïve lymphocytes typically enter the cortex of the lymph node via high endothelial venules (HEVs) of the blood stream. These specialized veins are lined with unusually tall endothelial cells that give them a thickened appearance (Figure 2-13a; and see Figure 14-2). The lymphocytes then squeeze between endothelial cells of the HEV, into the functional tissue of the lymph node.

Once naïve T cells enter the lymph node, they browse MHC–peptide antigen complexes on the surfaces of APCs in the paracortex, the lymph node’s T-cell zone. The APCs position themselves on a network of fibers that arise from stromal cells called fibroblastic reticular cells (FRCs) (Figure 2-14a). This fibroblastic reticular cell conduit (FRCC) system guides T-cell movements via associated adhesion molecules and chemokines. Antigen-presenting cells wrap themselves around the conduits, giving circulating T cells ample opportunity to browse their surfaces as they are guided down the network. The presence of this specialized network elegantly enhances the probability that T cells will meet their specific MHC-peptide combination (see also Chapter 14 opening figure, Figure 14-6, and associated Videos 14-Ov and 14-6v).

FIGURE 2-14 Stromal cell networks in secondary lymphoid tissue. T and B lymphocytes travel along distinct structures in secondary lymphoid microenvironments. (a) The paracortex is crisscrossed by processes and conduits formed by fibroblastic reticular cells (FRCs), which guide the migration of antigen-presenting cells and T cells, facilitating their interactions. Left: An immunofluorescence microscopy image with the FRCs shown in red and the T cells in green. Right: A drawing of the network and cell participants. (Abbreviations: DC = dendritic cell; HEV = high endothelial venule.) (b) The B-cell follicle contains a network of follicular dendritic cells (FDCs), which are shown (left) as an SEM image as well as (right) a drawing. FDCs guide the movements and interactions of B cells.

Section a – The scanning electron micrograph shows a dense network of vessels in one color and small spherical cells in another color. The drawing shows a network of vessels with irregular shaped cells, spherical cells, and fibroblastic reticular cells.

Section b- The scanning electron micrograph shows Follicular dendritic cell with raised centers and numerous fiber-like projections. The drawing shows multiple cells with long dendrites that touch other cells’ dendrites to form a network. Follicular dendritic cells and B cells are seen between the dendrites.

Although naïve T cells enter via the blood, they exit via the efferent lymphatics in the medulla of the lymph node (Figure 2-13a), if they do not find their MHC-peptide match. T cells expressing TCRs that bind an MHC-peptide complex stop migrating and take up residence in the node for several days. Here they proliferate and, depending on cues from the antigen-presenting cell itself, differentiate into effector cells with a variety of distinct functions. CD8⁺ T cells gain the ability to kill target cells. CD4⁺ T cells differentiate into several different kinds of effector cells, including those that further activate macrophages, CD8⁺ T cells, and B cells.

B Cells in the Lymph Node

The lymph node is also the site where B cells are activated and differentiate into high-affinity, antibody-secreting plasma cells. Optimal B-cell activation requires both antigen engagement by the B-cell receptor (BCR) and direct contact with an activated CD4⁺ T_H cell. Both events are facilitated by the anatomy of the lymph node. Like T cells, B cells circulate through the blood and lymph and visit the lymph nodes on a daily basis, entering via the HEVs. They respond to specific signals and chemokines that draw them not to the paracortex but to the lymph node follicles. Although they may initially take advantage of the FRCC system for guidance, they ultimately shift to tracts generated by follicular dendritic cells (FDCs) (Figure 2-14b). FDCs maintain follicular and germinal center structure and present particulate antigen to differentiating B cells.

B cells differ from T cells in that their receptors can recognize free, unprocessed antigen. A B cell typically meets its antigen in a lymph node follicle, or B-cell follicle. Small, soluble antigens can make their way directly into the follicle, whereas larger antigens are relayed to the follicular dendritic cells by subcapsular macrophages and non-antigen-specific B cells (see Chapter 14). If its BCR binds to antigen, the B cell becomes partially activated and engulfs the antigen and processes it, readying it for presentation as a peptide-MHC complex to CD4⁺ T_H cells.

B cells that have successfully engaged and processed antigen change their migration patterns and move to the T cell–rich paracortex, where they may encounter a previously activated CD4⁺ T_H cell. If this helper T cell recognizes the MHC-antigen complex presented by the B cell, the pair will maintain contact for a number of hours, during which the B cell receives signals from the T cell that induce B-cell proliferation and differentiation (see Figure 14-4 and accompanying videos).

Some activated B cells differentiate directly into antibody-producing cells (plasma cells), but others re-enter the follicle to establish a germinal center. A follicle that develops a germinal center is referred to as a secondary follicle; a follicle without a germinal center is referred to as a primary follicle. In germinal centers, B cells proliferate and undergo clonal selection (see Figure 1-6) to produce a colony of B cells with the highest affinity for a particular antigen. Some of these cells travel to the medulla of the lymph node and release antibodies into the bloodstream; others exit through the efferent lymphatics and take up long-term residence in the bone marrow, where they will continue to release antibodies into circulation.

Germinal centers are established within 4 to 7 days of the initial infection, but remain active for 3 weeks or more (Chapter 11). Lymph nodes swell visibly and sometimes painfully during those first few days after infection as immune cells migrate into the node and T and B cells proliferate.

The Generation of Memory T and B Cells in the Lymph Node

Interactions between T cells and APCs, and between activated T_H cells and activated B cells, result in the generation of memory T and B cells. Memory T and B cells either take up residence in secondary lymphoid tissues or exit the lymph node and circulate to and among other tissues, including those that first encountered the pathogen. Memory T cells that reside in secondary lymphoid organs are referred to as central memory cells and are distinct in phenotype and functional potential from effector memory T cells that circulate among tissues. A third population, tissue-resident memory cells, settle in peripheral tissues for the long term and appear to be the first cells to respond when an individual is re-infected with a pathogen. Memory cell phenotype, locale, and activation requirements are very active areas of investigation and will be discussed in more detail in Chapters 10 and 11.

Key Concepts:

• The lymph nodes organize the immune response to antigens that enter through lymphatic vessels. T cells and B cells are compartmentalized in different microenvironments in secondary lymphoid tissue. T cells are found in the paracortex of the lymph nodes, while B cells are organized in follicles in the cortex.
• Naïve T lymphocytes browse the surfaces of antigen-presenting cells in the T-cell zone or paracortex of the lymph node, guided by the FRC network. If they bind to an MHC-peptide combination, they are activated and undergo clonal expansion and differentiation into effector cells in secondary lymphoid organs. If they do not, they exit via the efferent lymphatics and continue browsing in other lymph nodes.
• T lymphocytes develop into mature killer CD8⁺ and helper CD4⁺ cells in secondary lymphoid organs. Some CD4⁺ T cells help B cells to differentiate into antibody-secreting plasma cells; others activate macrophages and CD8⁺ cytotoxic T cells.
• Naïve B cells that enter lymph nodes travel to B-cell follicles, where they meet their antigen on the FDC network. Those that bind antigen are activated, divide, and seek T-cell help. Those that do not exit the lymph node via the efferent lymphatics to browse another secondary lymphoid tissue.
• Activated B cells undergo further maturation into high-affinity, antibody-producing cells in specialized microenvironments called germinal centers, substructures that develop within B-cell follicles.
• B and T cells develop into long-lived memory cells in secondary lymphoid organs. Some memory cells remain in lymphoid tissue, some circulate, and some take up residence in other tissues, ready to respond quickly to a returning pathogen.

The Spleen Organizes the Immune Response against Blood-Borne Pathogens

The spleen, situated high in the left side of the abdominal cavity, is a large, ovoid secondary lymphoid organ that plays a major role in mounting immune responses to antigens in the bloodstream (Figure 2-15). Whereas lymph nodes are specialized for encounters between lymphocytes and antigen drained from local tissues, the spleen specializes in trapping and responding to blood-borne antigens; thus, it is particularly important in the response to systemic infections. Unlike lymph nodes, the spleen is not supplied by lymphatic vessels. Instead, blood-borne antigens and lymphocytes are carried into the spleen through the splenic artery and out via the splenic vein. Experiments with radioactively labeled lymphocytes show that more recirculating lymphocytes pass daily through the spleen than through all the lymph nodes combined.

FIGURE 2-15 Structure of the spleen. (a) The spleen, which is about 5 inches long in human adults, is the largest secondary lymphoid organ. It is specialized for trapping blood-borne antigens. (b) A stained tissue section of the human spleen, showing the red pulp, white pulp, and follicles. These microenvironments are diagrammed schematically in (c). The splenic artery pierces the capsule and divides into progressively smaller arterioles, ending in vascular sinusoids that drain back into the splenic vein. The erythrocyte-filled red pulp surrounds the sinusoids. The white pulp forms a sleeve—the periarteriolar lymphoid sheath (PALS)—around the arterioles; this sheath is populated by T cells. Closely associated with the PALS are the B cell–rich lymphoid follicles that can develop into secondary follicles containing germinal centers. The marginal zone, a site of specialized macrophages and B cells, surrounds the PALS and separates it from the red pulp.

Section a shows the outline of a human body with the following parts labeled: Adenoids, Tonsils, Lymph nodes, spleen, Peyer’s patches, bone marrow, Left subclavian vein, small intestine, tissue lymphatics, appendix, large intestine, thoracic duct, thymus, Right Subclavian vein, and Right lymphatic duct. A part of the small intestine is zoomed out and shown in the next section. Section b shows a stained tissue cross section of the intestinal cell. The stained region is labeled as GALT. A part of the epithelial layer is marked and zoomed out in the next section. Section c shows a drawing of the epithelial layer, which has M cells. Bacterial cells are shown above the outer layer of the cell. Some bacteria bind to the M cells. Plenty of T cells and B cells are formed in the Lamina propria region. Some bacteria entering lumen are phagocytosed by macrophages. Dendrite cells are also shown in the inner side of the epithelial layer. B cells trigger the formation of plasma cells that grow and form antibodies in the lumen. An arrow shows the emigration of some T, B, and A P Cs to the Mesenteric lymph node.

The spleen is surrounded by a capsule that extends into the interior, dividing the spleen into lobes, all of which function similarly. Two main microenvironmental compartments can be distinguished in each splenic lobe: the red pulp and white pulp, which are separated by a specialized region called the marginal zone (see Figure 2-15c). The splenic red pulp consists of a network of sinusoids populated by red blood cells, macrophages, and some lymphocytes. It is the site where old and defective red blood cells are destroyed and removed; many of the macrophages within the red pulp contain engulfed red blood cells or iron-containing pigments from degraded hemoglobin. It is also the site where pathogens first gain access to the lymphoid-rich regions of the spleen, known as the white pulp. The splenic white pulp surrounds the branches of the splenic artery, and consists of B-cell follicles and the periarteriolar lymphoid sheath (PALS), which is populated by T lymphocytes. As in lymph nodes, germinal centers are generated within these follicles during an immune response. The spleen also maintains a fibroblastic reticular network that provides tracts for T-cell and B-cell migration.

The marginal zone (MZ) is a specialized cellular border between the blood and the white pulp. A relatively recent development in the evolutionary history of the immune system, it is populated by specialized dendritic cells, macrophages, and unique B cells, referred to as marginal zone B cells (MZ B cells). These cells are the first line of defense against blood-borne pathogens, trapping antigens that enter via the splenic artery. Marginal zone B cells express both innate immune receptors (e.g., TLRs) and unique B-cell receptors that recognize conserved molecular patterns on pathogens. Once they bind antigen, MZ B cells differentiate rapidly and secrete high levels of antibodies. Although some MZ B cells require T-cell help for activation, others can be stimulated in a T cell–independent manner. Interestingly, mouse and human marginal zone anatomy differ, as does the phenotype and behavior of their marginal zone B cells. The basis for and significance of this species-specific difference are under investigation.

The events that initiate the adaptive immune response in the spleen are analogous to those that occur in the lymph node. Briefly, circulating naïve B cells encounter antigen in the follicles, and circulating naïve CD8⁺ and CD4⁺ T cells meet antigen as MHC-peptide complexes on the surface of dendritic cells in the T-cell zone (PALS). Once activated, CD4⁺ T_H cells then provide help to B cells, including some marginal zone B cells, and CD8⁺ T cells that have also encountered antigen. Some activated B cells, together with some T_H cells, migrate back into follicles and generate germinal centers. As in the lymph node, germinal center B cells can become memory cells or plasma cells, which circulate to a variety of tissues including the bone marrow.

Children who have undergone splenectomy (the surgical removal of a spleen) are vulnerable to overwhelming post-splenectomy infection (OPSI) characterized by systemic bacterial infections (sepsis) caused primarily by Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Although fewer adverse effects are experienced by adults, splenectomy can still lead to an increased vulnerability to blood-borne bacterial infections, underscoring the role the spleen plays in our immune response to pathogens that enter the circulation. Because the spleen also serves other functions in iron metabolism, platelet storage, and hematopoiesis, these are also compromised if it is removed.

Key Concepts:

• The spleen organizes the first immune response to blood-borne pathogens.
• The spleen is compartmentalized into the white pulp, which contains B and T lymphocytes, and the red pulp, which contains circulating red blood cells.
• The periarteriolar lymphoid sheath of the white pulp includes B-cell follicles and T-cell zones.
• The splenic marginal zone, a specialized region of macrophages and B cells, forms a boundary between the red and the white pulp and plays an important role in trapping and responding to blood-borne antigens.

Barrier Organs Also Have Secondary Lymphoid Tissue

Lymph nodes and the spleen are not the only organs with secondary lymphoid microenvironments. T-cell zones and lymphoid follicles are also found in barrier tissues, which include the skin and mucosal membranes of the digestive, respiratory, and urogenital tracts. Each of these organs is lined by epithelial cells. Our mucosal membranes are lined with a single epithelial layer, while our skin is protected by many layers of epithelial cells. Together, skin and mucosal membranes represent a surface area of over 400 m² (nearly the size of a basketball court) and are the major sites of entry for most pathogens.

These vulnerable membrane surfaces are defended by a group of organized lymphoid tissues known collectively as mucosa-associated lymphoid tissue (MALT). Lymphoid tissues associated with different mucosal areas are sometimes given more specific names: for instance, bronchus-associated lymphoid tissue (BALT), nasal-associated lymphoid tissue (NALT), gut-associated lymphoid tissue (GALT), and skin-associated lymphoid tissue (SALT).

Each of these tissues plays an important role in our innate immune defenses and recruits many different cell types to the effort. The epithelial cell layers provide more than just physical protection; they also respond actively to pathogens by secreting cytokines, chemokines, and even antimicrobial compounds. Many different types of immune cells reside in the deeper layers of barrier tissues and generate B-cell follicles. B cells that develop in these follicles tend to secrete IgA, which has the ability to cross epithelial barriers and interact with microbes in the lumen of our mucosal tracts.

Innate and adaptive immune cells in barrier organs not only organize our first response to invading pathogens, but they also play a critical role in maintaining tolerance to the diverse and abundant commensal microbes that contribute positively to our health. The distinct immune functions and cell residents of each barrier tissue are described in more detail in Chapter 13, but a preview of the organization of secondary lymphoid tissue in the intestine (GALT) is depicted in Figure 2-16.

FIGURE 2-16 Example of secondary lymphoid tissue in barrier organs: gut-associated lymphoid tissue (GALT). (a) The Peyer’s patch is a representative of the extensive GALT system that is found in the intestine. (b) A stained tissue cross-section of Peyer’s patch lymphoid nodules in the intestinal submucosa is schematically diagrammed in (c). The single layer of epithelial cells includes specialized cells, called M cells, that convey antigens from the intestinal lumen to the inner layers (lamina propria) of the intestinal wall. Here they trigger the formation of B-cell follicles, which generate antibody-producing plasma cells. The antibodies pass back into the intestinal lumen and bind to pathogens, protecting the intestinal wall from inflammation and invasion. Other cells, including macrophages, dendritic cells, and intraepithelial lymphocytes, sample antigens from the lumen and, with the help of regulatory T cells, work to distinguish between beneficial commensal bacteria and more dangerous pathogens. Antigen-presenting cells and lymphocytes can travel to local lymph nodes, where they trigger a more systemic immune response to antigens.

Section a shows the outline of a human body with the following parts labeled: Adenoids, Tonsils, Lymph nodes, spleen, Peyer’s patches, bone marrow, Left subclavian vein, small intestine, tissue lymphatics, appendix, large intestine, thoracic duct, thymus, Right Subclavian vein, and Right lymphatic duct. A part of the small intestine is zoomed out and shown in the next section. Section b shows a stained tissue cross section of the intestinal cell. The stained region is labeled as GALT. A part of the epithelial layer is marked and zoomed out in the next section. Section c shows a drawing of the epithelial layer, which has M cells. Bacterial cells are shown above the outer layer of the cell. Some bacteria bind to the M cells. Plenty of T cells and B cells are formed in the Lamina propria region. Some bacteria entering lumen are phagocytosed by macrophages. Dendrite cells are also shown in the inner side of the epithelial layer. B cells trigger the formation of plasma cells that grow and form antibodies in the lumen. An arrow shows the emigration of some T, B, and A P Cs to the Mesenteric lymph node.

Key Concepts:

• Barrier immune organs, which include the skin and mucosal tissues, contain secondary lymphoid tissue and mount an important first defense against pathogens that penetrate our epithelial layers. Epithelial cells play an active role and initiate the response of innate and adaptive immune cells, which can organize into B-cell follicles.
• Barrier immune systems also help us maintain tolerance to commensal microbes that coexist at our surfaces.

Tertiary Lymphoid Tissues Also Organize and Maintain an Immune Response

A site of active infection and immune activity is often referred to as a tertiary lymphoid tissue. Lymphocytes activated by antigen in secondary lymphoid tissue return to these areas (e.g., lung, liver, brain, skin) as effector cells and can also reside there as tissue-resident memory cells. Tertiary lymphoid tissues can generate new microenvironments that organize lymphocyte responses. The brain, for instance, establishes reticular systems that guide lymphocytes responding to chronic infection with the protozoan that causes toxoplasmosis. Organized aggregations of lymphoid cells are especially prominent at sites of chronic infection and highlight the intimate relationship between immune and nonimmune cells, as well as the plasticity of tissue anatomy. This plasticity is also illustrated by the evolutionary relationships among immune systems and organs (see Evolution Box 2-4).

EVOLUTION BOX 2-4

Variations on Anatomical Themes

All multicellular organisms defend themselves against pathogens, and all have innate systems of immunity (see Chapter 4). The adaptive immune system appeared about 500 million years ago, with the emergence of vertebrate animals. Only vertebrates generate antigen-specific receptors. Interestingly, however, the location, organization, and function of lymphoid tissues vary widely across the vertebrate subphylum.

Vertebrates range from jawless fishes (Agnatha, the earliest lineages, which are represented by the lamprey eel and hagfish), to cartilaginous fish (e.g., sharks and rays, also called elasmobranchs), which represent the earliest lineages of jawed vertebrates (Gnathostomata), to bony fish, amphibians, reptiles, birds, and mammals. If you view these groups as part of an evolutionary progression, you see that, in general, immune tissues and organs evolved by earlier orders have been retained as newer organs of immunity, such as lymph nodes, have appeared (Figure 1). All vertebrates, for example, have gut-associated lymphoid tissue (GALT), but only jawed vertebrates have well-developed thymi and spleens. All vertebrates have two different (B and T) lymphoid cell populations, suggesting that they were present in our common ancestor.

FIGURE 1 Evolutionary distribution of lymphoid tissues. The appearance and presence of primary and secondary lymphoid tissues in vertebrates over evolutionary time. (Abbreviations: GALT = gut-associated lymphoid tissue; Ma = million years ago.)

The horizontal axis shows time in millions of years ago from 600 million years ago to present time. The vertical axis shows Lymph nodes, Spleen, Thymus, and Gut-Associated Lymphoid Tissue. The Common vertebrate ancestor evolved around 600 million years ago. The approximate data in the timeline graph shows:

Lymph nodes: Dashed line from around 250 million years ago to about 100 million years ago and solid line from 100 million years till present time.

Spleen: Dashed line from before 600 million years ago to around 525 million years ago and solid line from 525 million years ago till present.

Thymus: Solid line from before 600 million years till present time.

GALT: Solid line from before 600 million years till present time.

T cells were the first cell population to express a diverse repertoire of antigen receptors, and their appearance is directly and inextricably linked to the appearance of the primary immune organ, the thymus. This dependence is reflected in organisms today: all jawed vertebrates have a thymus, and the thymus is absolutely required for the development of T cells. Recent studies indicate that even jawless vertebrates, including the lamprey, harbor distinct thymic-like (thymoid) tissue in their gill regions (Figure 2).

FIGURE 2 Thymic tissue in the lamprey eel. (a) Jawless vertebrates, including the lamprey eel, were once thought not to have a thymus. Recent work suggests, however, that they generate two types of lymphocytes analogous to B and T cells and have thymic tissue at the tip of their gills (b). The thymic tissue shown in (c) is stained for expression of CDA1, a gene specific for lymphocytes found in lampreys.

Section a shows a photo of a lamprey eel. One of its gills is marked and zoomed out in the next section. Section b shows a stained tissue with irregular outline and finger like projections in the middle region. One of the projections is marked and zoomed out in the next section. Section c shows a close view of the thymus projections with stained CDA1 gene areas in the tip of the projections.

In contrast, B-cell development is not bound to one particular organ. In many adult mammals, including mice and humans, B cells primarily develop in the bone marrow and mature further in the spleen. In cattle and sheep, B-cell maturation shifts from the fetal spleen to a patch of tissue embedded in the wall of the intestine called the ileal Peyer’s patch. The rabbit also uses gut-associated tissues, especially the appendix, as primary lymphoid tissue for important steps in the proliferation and diversification of B cells. Recent data suggest that the gut can act as a primary lymphoid organ for generating mature B lymphocytes in most vertebrates, even those that depend largely on the bone marrow.

The sites of B-cell development also vary among nonmammalian vertebrates. In jawless vertebrates, B lymphocyte–like cells develop in distinct regions (called typhlosoles) in the kidney and intestine. In sharks, B-cell development shifts from liver to kidney to spleen, and in amphibians and reptiles it shifts from liver and spleen to bone marrow. B-cell development in bony fish takes place primarily within the kidney. In birds, B cells complete their development in a unique lymphoid organ associated with the gut, the bursa of Fabricius (Figure 3).

FIGURE 3 The avian bursa. (a) Like most vertebrates, birds have a thymus, spleen, and lymph nodes. Although hematopoiesis occurs in their bone marrow, B-cell development takes place in a specialized organ, known as the bursa. The bursa is an outpouching of the intestine located close to the cloaca, the common end of the intestinal and genital tracts in birds. A stained tissue section of the bursa and cloaca is shown in (b).

Section a shows the outline of a bird with the internal organs exposed. Thymus (T-cell development), Bursa of Fabricus (B-cell development), and Intestines are labeled. Thymus and Bursa of Fabricus are shown in a different color to highlight stained areas. An arrow from Bursa points to the next section that shows a stained image of Bursa tissue.

Secondary lymphoid tissues appear to have increased in complexity throughout vertebrate evolution. The spleen is the most ancient secondary lymphoid organ, and lymph nodes are the most recent immune adaptation. Lymph nodes likely arose from tissue associated with lymphatic vessels and appeared first in reptiles and birds. Mammals have the most highly organized lymph nodes, which centralize participants in the adaptive immune response. Secondary lymphoid structures are also found throughout epithelial tissues in vertebrates and vary widely in locale (e.g., although rodents do not have tonsils, they do have well-developed lymphoid tissue at the base of the nose). The general structural and functional features of secondary lymphoid tissue are shared by most vertebrates, with at least one interesting exception: pig lymph nodes exhibit a striking peculiarity—they are “inverted” anatomically, so that the medulla of the organ, where lymphocytes exit the organ, is on the outside, and the cortex, where lymphocytes meet their antigen and proliferate, is on the inside. Lymphocytes exit via blood vessels, rather than via efferent lymphatics. The adaptive advantages, if any, of these odd structural variations are unknown, but the example reminds us of the remarkable plasticity of structure-function relationships within biological structures and the creative opportunism of evolutionary processes.

REFERENCES

• Boehm, T., I. Hess, and J. B. Swann. 2012. Evolution of lymphoid tissues. Trends in Immunology 33:315.
• Du Pasquier, A. L., and M. F. Flajnik. 2004. Evolution of the immune system. In: Fundamental Immunology, 5th ed., W. E. Paul, ed. Lippincott-Raven, Philadelphia.

Key Concept:

• Tissues that are sites of infection are referred to as tertiary tissues. These sites can also develop organized lymphoid microenvironments, including B-cell follicles.