Natural killer cells were discovered quite by accident when immunologists were measuring in vitro activity of tumor-
(a) Fas pathway
Granzyme B Perforin
Granzyme B Perforin
substrates apoptotic effectors substrates apoptotic effectors
Two pathways of target-cell apoptosis stimulated by CTLs. (a) The Fas pathway. Ligation of trimeric Fas units by CTL-borne Fas ligand leads to the association of the death domains of Fas with FADD, which in turn results in a series of reactions leading to apoptosis of the target cell. (b) The perforin/granzyme pathway. Granule exocytosis releases granzymes and perforin from the CTL into the space between the CTL and the target cell. Granzyme B enters the target cell in two ways: via perforin-generated pores, or by binding to mannose 6-phosphate receptors that are subsequently endocytosed. Granzyme B is then released into the cytoplasm in a perforin-dependent process. Cleavage of procaspase 8 by granzyme B activates a caspase cascade that results in the apoptotic death of the cell, and interaction of granzyme B with other targets can invoke mitochondrially mediated death pathways. [Adapted from M. Barry and C. Bleackley, 2002, Nature Reviews Immunology 2:401]
specific cells taken from mice with tumors. Normal unim-munized mice and mice with unrelated tumors served as negative controls. Much to the consternation of the investigators, the controls showed significant lysis of the tumor cells, too. Characterization of this nonspecific tumor-cell killing revealed that a population of large granular lymphocytes was responsible. The cells, which were named natural killer (NK) cells for their nonspecific cytotoxicity, make up 5%-10% of the recirculating lymphocyte population. These cells are involved in immune defenses against viruses and tumors. Because NK cells produce a number of immunolog-ically important cytokines, they play important roles in immune regulation and influence both innate and adaptive immunity. In particular, IFN-7 production by NK cells can affect the participation of macrophages in innate immunity by activation of the phagocytic and microbicidal activities. IFN-7 derived from NK cells can influence the TH1 versus Th2 commitment of helper T cell populations by its inhibitory effects on TH2 expansion, and stimulate TH1 development via induction of IL-12 by macrophages and dendritic cells. The Chediak-Higashi syndrome described in the Clinical Focus illustrates the disastrous consequences of a lack of NK cells.
NK cells are involved in the early response to infection with certain viruses and intracellular bacteria. NK activity is stimulated by IFN-a, IFN-p, and IL-12. In the course of a viral infection, the level of these cytokines rapidly rises, followed closely by a wave of NK cells that peaks in about 3 days (Figure 14-12). NK cells are the first line of defense against virus infection, controlling viral replication during the time required for activation, proliferation, and differentiation of CTL-P cells into functional CTLs at about day 7. The importance of NK cells in defense against viral infections is illustrated by the case of a young woman who completely lacked these cells. Even though this patient had normal T- and B-cell counts, she suffered severe varicella virus infections and a life-threatening cytomegalovirus infection.
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