Immunology. Richard Coico
response. They produce nitric oxide (NO) or reactive oxygen intermediates to protect against bacteria and viruses (discussed further in Chapter 3).
M2 macrophages are alternatively activated by exposure to cytokines such as IL‐4, IL‐10, or IL‐13. M2 macrophages produce either polyamines to induce proliferation or proline to induce collagen production. These macrophages are associated with wound healing and tissue repair.
Although associated with diverse names and locations, many of these cells share common features, such as the ability to bind and engulf particulate materials and antigens. Because of their location along capillaries, these cells are most likely to make first contact with invading pathogens and antigens and, as we shall see later, play a large part in the success of innate as well as adaptive immunity (also called acquired immunity). As noted above and discussed in detail in later chapters, another major function of the macrophages is to take up antigens, process them by denaturation or partial digestion, and present them, on their surfaces, to antigen‐specific T cells (i.e., the process of antigen presentation).
Figure 2.12. Cytokine‐promoted differentiation of naïve CD4+ T cells into TH subsets showing some of their characteristic transcription factors.
Dendritic Cells.
Dendritic cells (DCs) are critically important members of the innate immune system due to their highly efficient antigen‐presenting cells (APCs) (see Chapter 3). Like other innate immune cells, they recognize and phagocytize pathogens and other antigens but their ability to present antigens to T cells far exceeds that of other APCs. They are found as migrating DCs in the blood, nonmigratory follicular dendritic cells (fDCs) in primary and secondary follicles of the B cell areas of lymph nodes and spleen, interdigitating cells of the thymus, and Langerhans cells in the skin. Another type of dendritic cell is the plasmacystoid DC (pDC). Unlike other DC subpopulations that are derived from myeloid precursor cells, pDCs are derived from lymphoid precursors. Like all DCs, pDCs display antigen‐presenting function, but they are distinguished by their ability to produce large amounts of IFN‐α/β in response to viral and bacterial stimuli.
LYMPHOCYTE MIGRATION AND RECIRCULATION
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 TH 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