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Lymph nodes are highly efficient in trapping antigen that enters through the afferent lymphatic vessels (see Figure 2.5A). Within the lymph node, antigens interact with macrophages, T cells, and B cells, and that interaction brings about an immune response, manifested by the generation of antibodies and antigen‐specific T cells. Lymph, antibodies, and cells leave the lymph node through the efferent lymphatic vessel, which is just below the medullary region. Blood lymphocytes enter the lymph nodes through postcapillary venules and leave the lymph nodes through efferent lymphatic vessels, which eventually converge in the thoracic duct. The duct empties into the vena cava, the vessel that returns the blood to the heart, thus providing for the continual recirculation of lymphocytes.

The spleen functions in a similar manner. Arterial blood lymphocytes enter the spleen through the hilus and pass into the trabecular artery, which along its course becomes narrow and branched (see Figure 2.4A). At the farthest branches of the trabecular artery, capillaries lead to lymphoid nodules. Ultimately, the lymphocytes return to the venous circulation through the trabecular vein. Like lymph nodes, the spleen contains efferent lymphatic vessels through which lymph empties into the lymphatics from which the cells continue their recirculation through the body and back to the afferent vessels (see Figure 2.1).

The migration of lymphocytes between various lymphoid and nonlymphoid tissue and their homing to a particular site are highly regulated by means of various cell‐surface adhesion molecules (CAMs) and receptors to these molecules. Thus, except in the spleen, where small arterioles end in the parenchyma, allowing access to blood lymphocytes, blood lymphocytes must generally cross the endothelial vascular lining of postcapillary vascular sites, termed high endothelial venules (HEVs), to enter tissues. This process is called extravasation. Recirculating lymphocytes selectively bind to specific receptors on the HEVs of lymphoid tissue or inflammatory tissue spaces and appear to completely ignore other vascular endothelium. Moreover, it appears that a selective binding of finer specificity operates between the HEVs and various distinct subsets of lymphocytes, further regulating the migration of lymphocytes into the various lymphoid and nonlymphoid tissue. Recirculating monocytes and granulocytes also express adhesion molecule receptors and migrate to tissue sites using a similar mechanism.

Table 2.2. Properties of T_H Cell Subsets

Subset	Surface phenotype	Cytokines	Transcription factors	Functional attributes
TH1	αβ TCR, CD3, CD4	IFN‐γ, IL‐2, LTα	T‐bet, STAT4, STAT1	Promote protective immunity against intracellular pathogens; induce activation of macrophages and upregulation of iNOS, leading to the killing of intracellular pathogens
TH2	αβ TCR, CD3, CD4	IL‐4, IL‐5, IL‐13, IL‐10	GATA3, STAT6, DEC2, MAF	Promote humoral (antibody) immune responses and host defense against extracellular parasites; can potentiate allergic responses and asthma
TH17	αβ TCR, CD3, CD4	IL‐17A, IL‐17F, IL‐21, IL‐22	RORγt, STAT3, RORα	Promote protective immunity against extracellular bacteria and fungi, mainly at mucosal surfaces; can promote autoimmune and inflammatory diseases
TFH	αβ TCR, CD3, CD4, PD1	IL‐17A, IL‐17F, IL‐21, IL‐22	RORγt, STAT3, RORα	Involved in promotion of germinal center responses and provide help for B cell class switching
TReg	αβ TCR, CD3, CD4, CD25, CTLA4, GITR	IL‐10, TGFβ, IL‐35	FOXP3, STAT5, FOXO1, FOXO3	Promote immunosuppression and tolerance by contact‐dependent and ‐independent mechanisms. These cells are generated from naïve T cells in the periphery and, at least in some cases, TGF‐β and IL‐2 are important for their differentiation

Table 2.3. Innate Lymphoid Cell (ILC) Groups and Their Signature Cytokines

Group	Cytokines produced
ILC1	IFN‐γ Tumor necrosis factor (TNF)
ILC2	IL‐4 IL‐5 IL‐13
ILC3	IL‐22 IFN‐γ

The migration of lymphocytes between lymphoid and nonlymphoid tissue ensures that on exposure to an antigen, the antigen and lymphocytes expressing antigen‐specific receptors are sequestered in the lymphoid tissue, where the lymphocytes undergo proliferation and differentiation. This results in expansion of the antigen‐specific B‐cell population and the generation of circulating antibody‐secreting plasma cells as well as long‐lived, antigen‐specific memory B cells. The latter are disseminated throughout the secondary lymphoid tissues to ensure long‐lasting immunity to the antigen.

Figure 2.13. Scanning electron micrograph of macrophage with ruffled membrane and surface covered with microvilli (×5200).

Source: Reproduced with permission from J Clin Invest 117 [2007].