The growth of LGLs appears to be under the regulation of various cytokines, in particular IL-2. Early studies demonstrated that high concentrations of IL-2, in the absence of other stimuli such as antigens or mitogens, can stimulate the proliferation of LGLs but not T lymphocytes. Moreover, LGLs propagated in the presence of IL-2 retain potent cytolytic activity. The capacity of LGLs to respond directly to IL-2 is probably due to the high level of expression of the II.-2 receptor (3 chain. In addition to IL-2, interferon y is also capable of stimulating the growth of LGLs. These observations, combined with the fact that LGLs themselves can secrete cytokines, suggest that LGLs are important players in the cytokine network of the immune system.
The remarkable response of LGLs to IL-2 has made it possible to generate lymphokine-activated killer (LAK) cells in vitro. LAK cells, propagated primarily from LGLs/NK cells isolated from peripheral blood, contain more cytoplasmic granules and display a broader range of cytotoxicity against tumor cells than do their precursor LGLs. Similarly, the so-called 'tumor-infiltrating lymphocytes' (TILs), probably of CTL origin and with potent cytolytic activity, can be generated in culture in the presence of II.-2. These mighty killer cells, alone or in conjunction with IL-2, have been used in adoptive immunotherapy of advanced cancer.
Defects in LGL development, growth or functioning may result in clinical disorders. For example, aberrant proliferation of LGLs can lead to LGL leukemia. In addition to the expansion of l.GLs, patients with LGL leukemia often develop accom-panicd abnormalities such as neutropenia (decrease of neutrophils) and rheumatoid arthritis. Hypofunc-tion of LGLs/NK cells has been observed in patients with the Chediak-Higashi syndrome, a genetic disorder associated with fusion and defective degranu-lation of lysosomes and cytoplasmic granules in various types of granulated cells. As a consequcncc of granule dysfunction in hematopoeitic cells, these patients exhibit increased susceptibility to infections. In mice, the beige mutation results in a phenorype similar to that of the Chediak-Higashi syndrome, with anomalies in granule formation in LGLs/NK cells and reduced cytolytic capacity.
See also: Antibody-dependent cellular cytotoxicity; Cytokines; Cytotoxic T lymphocytes; Cytotoxicity, mechanisms of; Effector lymphocytes; Granzymes; Cell-mediated lysis; Immunotherapy of tumors; Innate immunity; Lymphocytes; Lymphokine-acti-
vated killer (LAK) cells; MHC restriction; Natural killer
(NK) cells; Perforin.
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