Interferon—A Major Regulator of Natural Killer Cell-Mediated Cytotoxicity

Abstract

Natural killer (NK) cells probably function as an early defense line against viruses because of their ability to kill virus-infected cells as well as a variety of tumor cells. In both cases, the killing is major histocompatibility complex (MHC»-unrestricted. NK cells exhibit spontaneous activity but they are positively regulated by interferons (IFNs) or indirectly by such IFN inducers as viruses, bacterial products, poly(rI):(rC), and mitogens. In addition to their "positive" regulation on NK activity, IFNs often act as "negative signals" for NK and lymphokine-activated killer (LAK) cell-mediated cytotoxicity. If NK susceptible target cells are exposed to IFN prior to NK cells, their sensitivity to NK activity is often markedly diminished. The mechanism by which IFNs (IFN-ct, -ß, and -y) affect the sensitivity of target cells to NK activity remains unknown, but it is clear that this function is not shared by other cell-mediated killing processes. The protective effect induced by IFN against NK activity is dependent on new mRNA and protein synthesis and can be abolished when target cells are incubated with a combination of IFN and metabolic inhibitors or by chemotherapeutic purine or pyrimidine analogs. IFN treatment neither affects the conjugate formation between NK cell and target cell nor the susceptibility of target cells to NK cytotoxic factor (NKCF), released by effector cells. However, IFN reduces the capacity of target cells to induce activation of conjugated NK cells. Because IFN has the ability to induce or increase class I MHC antigen expression (on NK target cells), it has been suggested that class I MHC antigens act as "negative signals" or NK-mediated cytotoxicity. Although many studies support this hypothesis, others present evidence for a lack of involvement of class I MHC antigens in mediating sensitivity to NK activity. This review summarizes and discusses the dual effect of IFNs in the regulation of NK activity, the relationship between the expression of class I MHC antigens on target cell surface and sensitivity to NK activity following treatment with IFNs, and the possible clinical relevance of the dual effect of IFN. e.g., lymphokine-activated killer (LAK) cells, also belong to the natural-immune arm. (1) NK cells can be identified unequivocally as a discrete subset of lymphocytes with characteristic morphologic, immunophenotypic, and functional attributes. NK lymphocytes are often associated with the morphologically identified population of the large granular lymphocytes (LGL). LGL comprise 5-10% of peripheral blood lymphocytes (PBL), they arise from precursors in bone marrow, and they exist in healthy, tumor-bearing, or infected individuals. Unlike cytotoxic T lymphocytes (CTL), NK cells kill the appropriate targets without clonal distribution and without requiring recognition

Interferon-α in acute myeloid leukemia: an old drug revisited

“…[38][39][40][41][42][43][44][45][46] In this context, IFN-a again emerges as a potentially useful agent because there is strong evidence for its ability to harness the cytolytic activity of NK cells (Table 1). 47 In addition, type I IFN can directly trigger the release of immunomodulatory cytokines from NK cells (for example, IFN-g), thereby potentiating the regulatory 'helper' function of these cells (Table 1). 30,[48][49][50][51][52] This helper role of NK cells is important for the induction of DC with potent T helper type 1-polarizing capacity, which appears to be critical for antitumor immunity.…”

Distinct Requirements for IFNs and STAT1 in NK Cell Function

“…NK cells are responsible for Ab-dependent cellular cytotoxicity (ADCC), 4 mediated through low affinity Fc␥ receptors. Therefore, we investigated whether ADCC was impaired by loss of STAT1.…”

“…Because of their rapid action, NK cells are one of the essential cell types forming the first line of host defense against microbial pathogens and tumors (1, 2) and play a major effector as well as regulatory role in antiviral defense (3). The function of NK cells, like other effector cells participating in innate immunity, such as granulocytes and macrophages/monocytes, is enhanced by cytokines, including IFN (4). In fact, in the early response to infection by viruses and certain microorganisms, IFNs are usually produced coordinately at the site of infection and the kinetics of IFN production correlate with NK cell activity, peaking at 3-5 days postinfection (5,6).…”

Increased Th1/Th2 (IFN-.GAMMA./IL-4) Cytokine mRNA Ratio of Rat Embryos in the Pregnant Mouse Uterus

“…Using a rodent interspecific pregnancy model established by embryo transfer between M. musculus and M. caroli, Clark et al [48] explained that the failure of immunocompetent M. musculus females to support the development of M. caroli embryos was due to the presence of activated n a t u r a l k i l l e r ( N K ) c e l l s t h a t s e l e c t i v e l y discriminate against M. caroli embryos early in pregnancy. In mice, NK cell-like granulated metrial gland cells in the uterus are a subset of lymphocytes belonging to the NK cell lineage [49], and IFN-γ activates NK cells and enhances cytotoxic activity [50,51]. The Th1-type cytokine IFN-γ also induces apoptosis of trophoblasts [52], abortion [53], and fetal resorption [24].…”