All viruses, and some bacteria, multiply in the cytoplasm of infected cells; indeed, a virus is a highly sophisticated parasite that has no biosynthetic or metabolic apparatus of its own and, in consequence, can replicate only inside cells. Although susceptible to antibody-mediated clearance before they enter cells, once they enter cells these pathogens are not accessible to antibodies and can be eliminated only by the destruction or modification of the infected cells in which they replicate. This role in host defense is largely filled by CD8 cytotoxic T cells, although TH1 cells may also acquire cytotoxic capacities. The crucial role of cytotoxic T cells in limiting such infections is seen in the increased susceptibility of animals artificially depleted of these T cells, or of mice or humans that lack the MHC class I molecules that present antigen to CD8 T cells. The elimination of infected cells without the destruction of healthy tissue requires the cytotoxic mechanisms of CD8 T cells to be both powerful and accurately targeted.
9-29 Cytotoxic T cells induce target cells to undergo programmed cell death via extrinsic and intrinsic pathways of apoptosis.
To deprive cytosolic pathogens of their cellular host, cytotoxic T cells target the infected host cells for death. Cells can die in various ways. Physical or chemical injury, such as the deprivation of oxygen that occurs in heart muscle during a heart attack or membrane damage with antibody and complement, leads to cell disintegration or necrosis. This form of cell death is often accompanied by local inflammation and stimulates a wound healing response. The other form of cell death is known as programmed cell death, which can occur by apoptosis or autophagy. Apoptosis is a regulated process that is induced either by specific extracellular signals or by the lack of signals required for survival, and proceeds by a series of cellular events that include plasma membrane blebbing, changes in the distribution of membrane lipids, and enzymatic fragmentation of chromosomal DNA. A hallmark of apoptosis is the fragmentation of nuclear DNA into pieces 200 base pairs long through the activation of nucleases that cleave the DNA between nucleosomes. As described in Chapter 6, autophagy is the process of degrading senescent or abnormal proteins and organelles. In autophagic cell death, large vacuoles degrade cellular organelles before the condensation and destruction of the nucleus that is characteristic of apoptosis.
Cytotoxic T cells kill by inducing their targets to undergo apoptosis (Fig. 9.41). Two general pathways are involved in signaling apoptotic cell death. One, called the extrinsic pathway of apoptosis, is mediated by the activation of so-called death receptors by extracellular ligands. Engagement of ligand stimulates apoptosis in receptor-bearing cells. The other pathway is known as the intrinsic or mitochondrial pathway of apoptosis and is induced in response to noxious stimuli (for example, ultraviolet irradiation or chemotherapeutic drugs), or lack of the growth factors required for survival. Common to both pathways is the activation of specialized proteases called aspartic acid-specific cysteine proteases, or caspases, which were introduced in Chapter 3 for their role in processing the cytokines IL-1 and IL-18 to their mature forms.