The three main APCs

Brief comments on three main APCs now follow. Macrophages are ubiquitous cells found in most tissues. They are highly active in internalization of a wide range of proteins as well as microorganisms. The extent of expression of class II MHC molecules varies among macrophages of various tissues and also among species. For example, most human monocytes and macrophages express class II MHC molecules, and are active in presenting antigens; in contrast class II MHC molecules are expressed on only a percentage of macrophages in the mouse. Here the percentage of class II-bearing cells varies from most of spleen macrophages to just a few of peritoneal macrophages. Accordingly, antigen presentation varies among them. Regardless, macrophages from all species express high levels of class II MHC molecules after their exposure to interferon y (IFNy).

Macrophages are highly effective in presentation of proteins and bacteria, most likely as a result of their highly developed endocytic capacity. They take up proteins by fluid-phase pinocytosis and/or receptor-mediated uptake, i.e. by their binding to specific surface receptors. Macrophages have complement receptors and Fc receptors that enable them to take up opsonized antigens as well as surface receptors for denatured proteins (scavenger receptors) or glycosylated proteins (such as the mannose receptor).

Macrophages are also highly secretory cells. Some of the secretory products are important during antigen presentation and early inductive events. These include interleukin la (IL-la) and ILfJ, tumor necrosis factor a (TNFa), IL-12, IL-6, IL-8 and a number of other chemokines. This group of early cytokines has effects on T cells as well as on connective tissue and vascular cells and they are believed to be involved in the early inflammatory changes in immunity. Macrophages also express adhesive and costimulatory molecules such as ICAM-1 (CD54), B7-1 (CD80) and B7-2 (CD86), respectively. Their level of expression is increased, particularly after the uptake of microbial antigens.

The Langerhans-dendritic cells constitute a single lineage, abundant in the skin and epithelia and thymus-dependent areas of lymphoid tissues, l.anger-hans cells are part of the family of dendritic cells (DCs). In the epidermis they constitute about 2-8% of the cells and are found between the keratinocytes, where they were first identified by morphological studies. Langerhans-dendritic cells arrive by way of afferent lymphatics to the thymic-dependent areas of lymphoid organs. In the skin they represent the local APC that takes up antigen molecules that contact the epidermis and carry the antigen by way of the lymphatic circulation to the draining lymph nodes. For example, application of protein-reactive compounds to the skin, such as dinitrofluorobenzene, ultimately results in their binding to the class II MHC of the Langerhans-dendritic cells, and with it the subsequent activation of T cells in the lymph nodes. Ultraviolet irradiation of the epidermis results in their disappearance; if such sensitizing compounds are applied to such areas, no T cell activation takes place.

DCs originate from bone marrow precursors, circulate, and seed the different lymphoid tissue and epithelia. DCs and macrophages have similar progenitors, with monocytes being a common cellular stage prior to the differentiation of the two lineages. In culture, the immature DC can differentiate to a mature state by the action of two cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4.

Another important immunological reaction where Langerhans-dendritic cells participate is in the allograft reaction. Their high content of MHC proteins make the Langerhans-dendritic cells the most powerful allogeneic cell in immunizing the host. Langerhans-dendritic cells are found in variable amounts in the interstitial and connective tissue of most transplanted organs (including liver, kidney, heart and, of course, skin).

DCs constitutively express high levels of class 11 MHC proteins, which makes them very active as APCs and as stimulator cells in the mixed leukocyte reaction. Langerhans-dendritic cells are active in presenting proteins but their degree of internalization and processing of protein antigens varies as a function of their state of maturation. As with macrophages, they mature in their antigen-presenting capacity. For example, their antigen-presenting capacity is limited when freshly harvested from the epidermis or blood but improves upon brief culture, which is one of the criteria for defining immature and mature DCs. DCs can express costimulatory molecules and release early cytokines such as IL-12.

B cells have an important antigen-presenting func tion that forms the basis for their interaction with T cells. B cells bind the specific antigen by way of their membrane immunoglobulin, internalize it and process it to peptides that become bound to their class II MHC molecules. The encounter with T cells reactive to the peptides results in a reciprocal activation of both cells. B cells function best as APCs if they are first activated, as they express only small amounts of costimulatory and adhesion molecules in their resting state. In vitro B cells become active in antigen presentation upon culture with anti-immunoglobulin antibodies and cytokines such as IFNy. Such treatment does not affect the level of class II MHC on B cells but increases the level of adhesion molecules, including ICAM and of B7-1 and B7-2. Expression of class II MHC molecules is constitutive in B cells. This basal level is increased by IL-4 but not by IFNy.

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