In infections by intracellular microbes, the killing activity of CTLs is important for eradicating the reservoir of infection (see Fig. 1B). This is particularly important in two types of situations when cells cannot destroy microbes that infect them. First, most viruses live and replicate in cells that lack the phagosome/ lysosome machinery for destroying microbes (such as hepatitis viruses in liver cells). Second, even in phagocytes, some microbes escape from vesicles and live in the cytosol, where microbicidal mechanisms are ineffective because these mechanisms are largely restricted to vesicles (to protect the host cells from damage). Bacteria such as Mycobacterium tuberculosis, Listeria monocytogenes and Rickettsial species are examples of microbes that escape from vesicles and enter the cytosol of infected cells. Such viral and bacterial infections can be eliminated only by destroying the infected cells, and in adaptive immune responses, CD8+ CTLs are the principal mechanism for killing infected cells. In addition, the caspases that are activated in target cells by granzymes and FAS-L cleave many substrates and activate enzymes that degrade DNA, but they do not distinguish between host and microbial molecules. Therefore, by activating nucleases in target cells, CTLs can initiate the destruction of microbial DNA as well as the target cell genome, thereby eliminating potentially infectious DNA. The massive expansion of CD8+ T cells that follows infections (see Fig. 2) provides a large pool of CTLs to combat these infections. Defects in the development and activity of CTLs result in increased susceptibility to viral and some bacterial infections and reactivation of latent virus infections (such as infection by the Epstein-Barr virus) that are normally kept in check by virus-specific CTLs.
Fig1. Role of T cells in eradicating infections. (A) CD4+ T cells recognize antigens of phagocytosed and extracellular microbes and produce cytokines and cell surface molecules that recruit and activate the phagocytes to kill the microbes. CD8+ T cells can also secrete some cytokines and participate in similar reactions (not shown). (B) CD8+ cytotoxic T lymphocytes (CTLs) recognize antigens of microbes residing in the cytoplasm of infected cells and kill the cells.
Fig2. Clonal expansion of T cells. The numbers of CD4+ and CD8+ T cells specific for microbial anti gens and the expansion and decline of the cells during immune responses are illustrated. The numbers are approximations based on studies of T-cell responses in inbred mice. The relative numbers of viable infectious organisms in an individual over time is indicated by the tan-shaded curve (not related to the number of T cells).
Destruction of infected cells by CTLs is a cause of tissue injury in some infectious diseases. For instance, in infection by hepatitis B and C viruses, the infected liver cells are killed by the host CTL (and NK cell) response and not by the viruses. These viruses are not highly cytopathic, but the host senses and reacts against the infectious microbe and is not able to distinguish microbes that are intrinsically harmful or relatively harmless. CTLs may contribute to the immunopathology associated with many other common viral infections, such as influenza.
CTLs are also important mediators of tumor immunity. In addition to their protective roles, CD8+ CTLs contribute to tissue destruction in some autoimmune diseases and to the rejection of tissue grafts. Surprisingly, granzyme K produced by CD8+ T cells may cleave some complement proteins and activate the complement pathway, thus contributing to complement-mediated tissue injury and inflammation.
Inherited mutations that interfere with CTL function, such as mutations in perforin and in genes encoding proteins involved in granule exocytosis, are associated with the rare familial dis ease called familial hemophagocytic lymphohistiocytosis (HLH) (see Chapter 21). HLH shares clinical features with secondary HLH, also known as macrophage activation syndrome, which can occur during a flare of a rheumatological disease, such as juvenile idiopathic arthritis, or a severe viral, bacterial, or fungal infection. In these disorders, CTLs that are activated by antigens secrete IFN-γ, but they do not kill the antigen producing cells because they cannot deliver the lethal hit. Thus, there is persistence of antigens, chronic IFN-γ production from the CD8+ T cells, and excessive macrophage activation by the IFN-γ. NK cells with defective killing function also likely con tribute to the excess IFN-γ production and macrophage activation in familial HLH. The severe and prolonged macrophage activation underlies the manifestations of the disease, including enlargement of the spleen caused by increased numbers of activated macrophages (lymphohistiocytosis) that phagocytose and destroy normal red blood cells (hemophagocytosis). An antibody that blocks IFN-γ has been approved for the treatment of macrophage activation syndrome, and JAK inhibitors are being tested in HLH.
CD4+ T cells that express granzymes and have cytotoxic functions have also been described and are discussed briefly in Chapter 10.
