Natural Killer Cells Natural killer cells are effector cells in an innate type of immune response: the nonspecific killing of tumor cells and virus-infected cells. Therefore, NK activity represents an innate form of immunity that does not require an adaptive, memory response for optimal biologic function, but the antitumor activity can be increased by exposure to several agents, particularly cytokines such as interleukin-2 (IL-2). Characteristically, NK cells have a large granular lymphocyte morphology. NK cells display a pattern of cell surface markers that differs from those characteristic of T or B cells. NK cells can express a receptor for the crystallizable fragment (Fc) portion of antibodies, and other NK-associated markers. NK cells appear to be functionally and phenotypically heterogeneous, when compared with T or B cells. The cells that can carry out antibody-dependent cellular cytotoxicity, or antibody-targeted cytotoxicity, are NK-like cells. Antibody-dependent cellular cytotoxicity by NK-like cells resulted in the lysis of tumor cells in vitro. The mechanisms of this tumor cell killing are not clearly understood, although close cellular contact between the effector cell and the target cell seems to be required.
Cytokines, Lymphokines, and Immune Mediators
Many events in the generation of immune responses (as well as during the effector phase of immune responses) require or are enhanced by cytokines, which are soluble mediator molecules (Table 6.5) (77–92). Cytokines are pleiotropic in that they have multiple biologic functions that depend on the type of target cell or its maturational state. Cytokines are heterogeneous in the sense that most cytokines share little structural or amino acid homology. Cytokines are called monokines if they are derived from monocytes, lymphokines if they are derived from lymphocytes, interleukins if they exert their actions on leukocytes, or interferons (IFNs) if they have antiviral effects. They are produced by a wide variety of cell types and seem to have important roles in many biologic responses outside the immune response, such as inﬂammation or hematopoiesis. They may also be involved in the pathophysiology of a wide range of diseases and show great potential as therapeutic agents in immunotherapy for cancer. Although cytokines are a heterogeneous group of proteins, they share some characteristics. For instance, most cytokines are low-to intermediate-molecular weight (10–60 kd) glycosylatedsecreted proteins. They are involved in immunity and inﬂammation, are produced transiently and locally (they act in an autocrine and paracrine rather than an endocrine manner), are extremely potent in small concentrations, and interact with high-affinity cellular receptors that are specific for each cytokine. The cell surface binding of cytokines by specific receptors results in signal transduction followed by changes in gene expression and, ultimately, by changes in cellular proliferation or altered cell behavior, or both. Their biologic actions overlap, and exposure of responsive cells to multiple cytokines can result in synergistic or antagonistic biologic effects.
Table 6.5 Sources, Target Cells, and Biological Activities of Cytokines Involved in Immune Responses
IL-1, interleukin-1; TH1, type 1 T-helper lymphocyte; NK cells, natural killer cells; TH2, type 2 T-helper lymphocyte; IgE, immunoglobulin E; MHCII, major histocompatibility complex class II; Ag, antigen; IFN, interferon; TNF, tumor necrosis factor. Modified from Berek JS, Martinez-Maza O. Immunology and immunotherapy. In: Lawton FG, Neijt JP, Swenerton KD. Epithelial cancer of the ovary. London, Engl.: BMJ, 1995:224, with permission.
T-cell subsets characterized by the secretion of distinct patterns of cytokines were identified.