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FIGURE 10-6 Cell-mediated immunity to Listeria monocytogenes. Immunity to L. monocytogenes is measured by inhibition of bacterial growth in the spleens of animals inoculated with a known dose of viable bacteria. Such immunity can be transferred to normal mice by T lymphocytes (A) but not by serum (B) from syngeneic mice previously immunized with killed or low doses of L. monocytogenes. In an in vitro assay of cell-mediated immunity, the bacteria are actually killed by activated macrophages and not by T cells (C).

FIGURE 10-6 Cell-mediated immunity to Listeria monocytogenes. Immunity to L. monocytogenes is measured by inhibition of bacterial growth in the spleens of animals inoculated with a known dose of viable bacteria. Such immunity can be transferred to normal mice by T lymphocytes (A) but not by serum (B) from syngeneic mice previously immunized with killed or low doses of L. monocytogenes. In an in vitro assay of cell-mediated immunity, the bacteria are actually killed by activated macrophages and not by T cells (C).

activated macrophages, emphasizing the central role of macrophages in the execution of effector function.

At any site of infection, as part of the innate immune response, monocytes are recruited from blood into tissues by chemokines produced by macrophages and other cells resident at the site (see Chapter 4). These monocytes mature into tissue macrophages and first attempt to phagocytose and destroy the pathogen. If the microbe has evolved to resist elimination by the macrophages, it survives within the phagosomes. In these infected cells, microbial peptides are processed and presented as peptides associated with class II MHC molecules. At the same time, Th1 effector cells are generated in an adaptive immune response in secondary lymphoid tissues, by processes described in Chapter 9. These T cells are recruited to the site of infection, where they recognize antigenic peptides (the same as those that initiated the response) displayed by the microbe-bearing macrophages. The macrophages are exposed to signals from the TH1 effector cells, which activate the macrophages to kill the ingested microbes. Activation consists of increased expression of various proteins that endow activated macrophages with the capacity to perform specialized functions, such as microbial killing. In the following sections, we describe the T cell signals that activate macrophages in cellmediated immune reactions and the functions of these macrophages.

CD4+ Th1 cells activate macrophages by contact-mediated signals delivered by CD40L-CD40 interactions and by IFN-y (Fig. 10-7). When the TH1 cells are stimulated by antigen, the cells express CD40L on their surface and secrete IFN-y. The actions of IFN-y on macrophages, described earlier, synergize with the actions of CD40 ligand, and together they are potent stimuli for macrophage activation. The importance of the CD40 pathway in cell-mediated immunity is illustrated by the immunologic defects in humans with inherited mutations in CD40L (X-linked hyper-IgM syndrome) and in mice in which the gene for CD40 or CD40L is knocked out (see Chapter 20). All these disorders are characterized by severe deficiencies in cell-mediated immunity to intracellular microbes, and children with the X-linked hyper-IgM syndrome often succumb to infection by the intracellular pathogen Pneumocystis jiroveci. As expected, these patients and knockout mice also have defects in helper T cell-dependent antibody production. The requirement for interactions between the surface molecules CD40 on the macrophages and CD40L on the T cells ensures that macrophages that are presenting antigens to the T cells (i.e., the macrophages that are harboring intracellular microbes) are also the macrophages that are most efficiently activated by the T cells. The role of IFN-y as the major macrophage-activating cytokine was discussed before. The same principles are applicable to the T cell-dependent activation of B lymphocytes—helper T cells stimulate B lymphocyte proliferation and differentiation by CD40-mediated signals and cytokines (see Chapter 11).

Activated macrophages kill phagocytosed microbes mainly by the actions of reactive oxygen species, nitric oxide, and lysosomal enzymes. All these potent microbicidal agents are produced within the lysosomes of macrophages and kill ingested microbes after phagosomes fuse with lysosomes (see Chapter 4, Figure 4-12). These toxic substances may also be released into adjacent tissues, where they kill extracellular microbes and may cause damage to normal tissues. This pathway of macrophage activation is called classical (Fig. 10-8) to distinguish it from alternative activation, described later.

Activated macrophages are involved in several other reactions of host defense (see Fig. 10-7). They stimulate

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