A nonsecretable cell surface mutant of tumor necrosis factor (TNF) kills by cell-to-cell contact

Perez, Carl F.; Albert, Iris; DeFay, Kim; Zachariades, Nicholas A.; Gooding, Linda R.; Kriegler, Michael

doi:10.1016/0092-8674(90)90158-b

Cited by 386 publications

(219 citation statements)

References 28 publications

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“…As shown in Fig. 1A proliferative activities of tmTNF CD4 1 T cells and wtTNF CD4 1 T cells were comparable, although at higher anti-CD3e concentrations, 3 H-TdR uptake was decreased in wtTNF T cells. To assess the proliferative behavior on a single cell level in vitro, unfractionated spleen cells from wtTNF and tmTNF mice were labeled with CFSE and stimulated with anti-CD3e.…”

Section: Results Wttnf and Tmtnf Cd4 1 T Cells Show Comparable Prolifmentioning

confidence: 61%

“…The generation of non-cleavable mutants of TNF revealed that tmTNF and sTNF exert distinct biological functions. A main function ascribed to tmTNF is the induction of cell death [3]. Some of the proinflammatory effects ascribed to TNF are also mediated by tmTNF as shown by the tmTNF-induced up-regulation of ICAM-1 and VCAM-1 on endothelial cells in vitro [4].…”

Section: Introductionmentioning

confidence: 99%

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Soluble TNF‐α but not transmembrane TNF‐α sensitizes T cells for enhanced activation‐induced cell death

et al. 2009

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In addition to its proinflammatory effects, TNF-a exhibits immunosuppression. Here, we compared the capacities of transmembrane TNF-a (tmTNF) and soluble TNF-a (sTNF) in regulating expansion of activated T cells by apoptosis. Splenic CD4 1 T cells from wtTNF, TNF-a-deficient (TNF À/À ) and TNF À/À mice expressing a non-cleavable mutant tmTNF showed comparable proliferation rates upon TCR-mediated stimulation. Activationinduced cell death (AICD), however, was significantly attenuated in tmTNF and TNF À/À , compared with wtTNF CD4 1 T cells. Addition of sTNF during initial priming was sufficient to enhance susceptibility to AICD in tmTNF and TNF À/À CD4 1 T cells to levels seen in wtTNF CD4 1 T cells, whereas addition of sTNF only during restimulation failed to enhance AICD. sTNF-induced, enhanced susceptibility to AICD was dependent on both TNF receptors. The reduced susceptibility of tmTNF CD4 1 T cells for AICD was also evident in an in vivo model of adoptively transferred CD4 1 T-cell-mediated colonic inflammation. Hence, the presence of sTNF during T-cell priming may represent an important mechanism to sensitize activated T cells for apoptosis, thereby attenuating the extent and duration of T-cell reactivities and subsequent T-cell-mediated, excessive inflammation.Key words: Activation-induced cell death . CD4 1 T cells . Colitis . TNF-a .Transmembrane TNF IntroductionTNF is a pleiotropic cytokine involved in innate and adaptive immunity. It is regarded as the prototypic proinflammatory cytokine and is crucial in immune defense against many pathogens but also during development of various autoimmune diseases [1]. The type I transmembrane 26 kDa precursor TNF molecule (tmTNF) is preferentially cleaved by the extracellular metalloproteinase TNF-a-converting-enzyme (TACE) to release trimers of the 17 kDa soluble form (sTNF) [2]. The generation of non-cleavable mutants of TNF revealed that tmTNF and sTNF exert distinct biological functions. A main function ascribed to tmTNF is the induction of cell death [3]. Some of the proinflammatory effects ascribed to TNF are also mediated by tmTNF as shown by the tmTNF-induced up-regulation of ICAM-1 and VCAM-1 on endothelial cells in vitro [4]. Mice overexpressing a non-cleavable tmTNF mutein are prone to develop arthritis [5] and signs of hepatitis after Concanavalin A (Con A) administration [6]. tmTNF transgenic mice [4] and tmTNF knock-in mice [7] are, in contrast to wtTNF mice, protected from LPS-induced death, thus demonstrating the distinct roles exerted by tmTNF and secreted TNF. Treatment of mice with a synthetic TACE inhibitor also protects mice from endotoxin-mediated death [8], indicating that TACE may represent a target to prevent the fatal effects of excessive sTNF production while maintaining the local TNF-mediated effects required in the host response against intracellular pathogens. The fact that tmTNF mice, but not TNF-deficient mice, are still capable of forming granulomas following infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG) and thu...

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Section: Results Wttnf and Tmtnf Cd4 1 T Cells Show Comparable Prolifmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Soluble TNF‐α but not transmembrane TNF‐α sensitizes T cells for enhanced activation‐induced cell death

et al. 2009

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“…(2,17,23,24). The observation that mTNF also can transmit reverse signals may have considerable implications for the therapeutic or prophylactic interference with TNF-triggered inflammation.…”

Section: Discussionmentioning

confidence: 99%

Reverse Signaling Through Transmembrane TNF Confers Resistance to Lipopolysaccharide in Human Monocytes and Macrophages

Eißner

Kirchner

Lindner

et al. 2000

The Journal of Immunology

176

129

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We have previously reported that the CD14+ monocytic subpopulation of human PBMC induces programmed cell death (apoptosis) in cocultured endothelial cells (EC) when stimulated by bacterial endotoxin (LPS). Apoptosis is mediated by two routes, first via transmembrane TNF-α (mTNF) expressed on PBMC and, in addition, by TNF-independent soluble factors that trigger apoptosis in EC. Neutralizing anti-TNF mAb completely blocked coculture-mediated apoptosis, despite the fact that there should have been additional soluble cell death factors. This led to the hypothesis that a reverse signal is transmitted from the TNF receptor on EC to monocytes (MO) via mTNF that prevents the production of soluble apoptotic factors. Here we have tested this hypothesis. The results support the idea of a bidirectional cross-talk between MO and EC. Peripheral blood MO, MO-derived macrophages (MΦ), or the monocytic cell line Mono Mac 6 were preincubated with human microvascular EC that constitutively express TNF receptor type I (TNF-R1) and subsequently stimulated with LPS. Cell-free supernatants of these preparations no longer induced EC apoptosis. The preincubation of MO/MΦ with TNF-reactive agents, such as mAb and soluble receptors, also blocked the production of death factors, providing further evidence for reverse signaling via mTNF. Finally, we show that reverse signaling through mTNF mediated LPS resistance in MO/MΦ as indicated by the down-regulation of LPS-induced soluble TNF and IL-6 as well as IL-1 and IL-10.

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“…Growth factors synthesized as large precursors that remain associated with the plasma membrane include EGF (Gray et al, 1983;Mroczkowski et al, 1989), TGF-a (Derynck et al, 1984;Lee et al, 1985), CSF-1 (Stein et al, 1990), TNF-a (Perez et al, 1990), kit-ligand (Anderson et al, 1990), vaccinia virus growth factor (VGF) (Stroobant et al, 1985), and amphiregulin (Plowman et al, 1990). An advantage of this type of restriction on growth factor action is that during processes such as development, hematopoiesis, and cell killing, discrete signaling might occur that requires stimulation of one cell type exclusively by adjacent cells (Perez et al, 1990;Stein et al, 1990). A diffusible factor would not be appropriate in such cases, whereas the membrane-inserted forms of growth factors would have a very restricted action.…”

Section: Regulation In Time and Spacementioning

confidence: 99%

The extracellular regulation of growth factor action.

Flaumenhaft

Rifkin

1992

MBoC

163

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A nonsecretable cell surface mutant of tumor necrosis factor (TNF) kills by cell-to-cell contact

Cited by 386 publications

References 28 publications

Soluble TNF‐α but not transmembrane TNF‐α sensitizes T cells for enhanced activation‐induced cell death

Soluble TNF‐α but not transmembrane TNF‐α sensitizes T cells for enhanced activation‐induced cell death

Reverse Signaling Through Transmembrane TNF Confers Resistance to Lipopolysaccharide in Human Monocytes and Macrophages

The extracellular regulation of growth factor action.

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