Environmental signals influencing expression of the IFN-gamma receptor on human T cells control whether IFN-gamma promotes proliferation or apoptosis.

Abstract

IFN-gamma R expression is subject to contrasting modulation on human T cells. IFN-gamma R constitutive expression is low on three human malignant T cells (ST4, PF382, and Jurkat) growing in medium supplemented with serum. The addition of IFN-gamma down-modulates IFN-gamma R expression and increases both proliferation and MHC class I Ag expression. By contrast, when malignant T cells are cultured in medium without serum, IFN-gamma R expression dramatically increases and the cells undergo a slow apoptotic death. The addition of IFN-gamma enhances apoptosis and inhibits cell rescue in serum-supplemented medium. This opposite ability of IFN-gamma to stimulate malignant T cell proliferation or death correlates with the intensity of IFN-gamma R cell expression, high expression being a marker for cell apoptosis. IFN-gamma R up-modulation also occurs on malignant T cells undergoing apoptosis after treatment with dexamethasone, on irradiated normal CD3+ PBL, and on cultured normal CD3+ thymocytes. Moreover, the ability of IFN-gamma to augment apoptosis of highly IFN-gamma R-positive thymocytes suggests that its role in promoting T cell apoptosis is also important in physiologic conditions.

DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity

“…Programmed cell death (PCD) can be triggered externally through the activation of various cell surface receptors. Among the physiological triggers of PCD, a group of cytokines plays a crucial role, including both diffusible cytokines such as TNF‐α, interferon‐γ (IFN‐γ) and TGF‐β, and membrane‐bound proteins such as the ligand to Fas/APO‐1 receptor (Laster et al ., 1988; Trauth et al ., 1989; Itoh et al ., 1991; Lin and Chou, 1992; Novelli et al ., 1994). These findings led to the concept that exposure of cell cultures to a specific cytokine may provide a well‐controlled in vitro system for the isolation of genes that mediate PCD.…”

“…Antibodies were raised and the and membrane-bound proteins such as the ligand to Fas/ expression of the proteins was studied. It was found that APO-1 receptor (Laster et al, 1988;Trauth et al, 1989;Itoh et al, 1991;Lin and Chou, 1992;Novelli et al, DAP-1 codes for a 15 kDa proline-rich basic protein, that DAP-2 is a structurally unique 160 kDa serine/threonine Immunostaining and biochemical fractionations revealed that the kinase is localized to the cytoskeleton in associ-protein kinase (therefore named DAP-kinase), and that DAP-3 codes for a 46 kDa protein that carries a potential ation with the microfilament system and defined a region downstream of the first P-loop motif which contributes to ATP/GTP binding motif Kissil et al, 1995).…”