To generate the small peptides, inhaled, ingested, or injected antigens are internalized by specialized antigen-presenting cells (APCs) and processed in an endocytic pathway.

APCs can be divided into “professional” and “amateur” subsets. Professional APCs such as monocytes, macrophages, dendritic cells, and B cells are fully committed to antigen presentation as an integral part of their function in the generation of the immune response. Other cells such as endothelial cells, fibroblasts, glial cells, pancreatic β- cells, keratinocytes, and thyroid cells present antigens only under select conditions. These cells are considered “amateur” APCs.

Professional Antigen-Presenting Cells

Monocytes and Macrophages

Monocytes and macrophages are responsible for the digestion of foreign material and for the presentation of antigenic epitopes to immunocompetent cells. Monocytes circulate in the blood, whereas macrophages are found in most tissues, for example, the brain (microglia), bone (osteoclasts), and connective tissue (histiocytes). Kupffer cells in the liver are the largest concentration of macrophages in the body.

Macrophages participate in both innate and adaptive immune responses. As part of innate immunity, macrophages are activated by antigens that are bound to PAMP, Toll-like, scavenger, and mannose receptors. In an adaptive response, antigens are recognized using receptors for intermediary molecules, such as antibody and complement fragments.

Dendritic Cells

In 1973, Steinman described a rare peripheral blood cell with membrane dendrites similar to a neuron. Other studies demonstrated that the dendritic cell (DC) is a “professional” antigen-producing cell present in lymphoid and nonlymphoid tissues. Dendritic cell precursors arise in bone marrow from committed CD34+ stem cells; differentiate into immature myeloid, monocytic, and lymphoid DCs; and are seeded into blood. Because of heterogeneity in cell surface markers, populations of DCs are difficult to identify. However, a putative hematopoietic differentiation pathway for DCs is shown in Figure 5-1.

Several DC subsets localize in tissues or circulate in peripheral blood. Two populations of dendritic cells are derived from a myeloid stem cell: (1) One population migrates to the lymph node where it becomes follicular dendritic cells. (2) A second population is found in nonlymphoid tissue and is referred to as interstitial dendritic cells. Lymphoid or plasmacytoid dendritic cells localize in the T cell compartment within the lymph node. Monocyte precursors may remain in peripheral blood as monocytic dendritic cells, although this concept is still being debated.

Dendritic cells are uniquely suited for antigen presentation. High numbers are concentrated at likely sites of microbial entry into the body (e.g., intestine and respiratory tract). Most DCs can efficiently capture and process antigen for presentation to T cells. Moreover, they are mobile and can migrate through tissue or stimulate immune responses in the regional lymph nodes.

Follicular Dendritic Cells

Follicular dendritic cells (FDCs) are found in the lymph node germinal follicles (Figure 5-2) and have several different functions, including activation of B cells and maintenance of immunologic memory.

Figure 5-2 The functions of the germinal center are clonal proliferation, somatic hypermutation of immunoglobulin receptors, receptor editing, isotype class switching, affinity maturation, and selection by antigen. In this model, the germinal center is composed of three major zones: (1) a dark zone, (2) a basal light zone, and (3) an apical light zone. These zones are predominantly occupied by centroblasts, centrocytes, and secondary blasts, respectively. Primary B cell blasts carrying surface immunoglobulin receptors (sIg+) enter the follicle and leave as memory B cells or antibody forming cells (AFCs). Antigen-presenting follicular dendritic cells (FDCs) are mainly found in the two deeper zones, and cell death by apoptosis occurs primarily in the basal light zone, where tingible body macrophages are also located. Blue squares are iccosomes on the FDC. (Adapted from Delves PJ, et al: Roitt’s essential immunology, ed 11, 2006, Blackwell Publishing.)

Unlike other DCs, FDCs do not process antigen for presentation to T cells. Rather, they stimulate a CD4Th2 response and maintain memory by a unique mechanism. Using a repertoire of receptors, FDCs bind processed and unprocessed antigens onto beaded, three-dimensional structures called iccosomes (Figure 5-3).