Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis.

An immunodominant epitope of myelin basic protein (MBP), VHFFKNIVTPRTP (p87-99), is a major target of T cells in lesions of multiple sclerosis (MS) and in experimental allergic encephalomyelitis (EAE). T cells found in EAE lesions bear the same amino acids in the third complementary determining region of the T cell receptor (TCR) as those found in MS lesions. We analyzed the trimolecular interactions between MBP p87-99, class II major histocompatibility complex (MHC), and TCR, and designed soluble inhibitors for therapy. F, N, I, and V at positions 90, 92, 93, and 94 interact with MHC, whereas K, T, and P at positions 91, 95, and 96 interact with TCR. The peptides, p87-99[95T > A] and p87-99[96P > A] could compete more effectively with p87-99 for binding to MHC and could antagonize the in vitro response to T cells to p87-99 more effectively than p87-99[91K > A]. However, only p87-99[91K > A] prevented and reversed EAE, indicating that the extent of MHC or TCR competition does not predict success in treating EAE. To elucidate the mechanism of inhibition of EAE, draining lymph node cells from rats immunized with the native peptide alone or together with each of the three TCR antagonists were challenged in vitro with p87-99. Administration of p87-99[91K > A], but not p87-99 [95T > A] or p87-99[96P > A], reduced the production of tumor necrosis factor (TNF)- alpha and interferon (IFN) gamma. IFN-gamma and TNF-alpha are two cytokines that are critical in the pathogenesis of EAE and MS.

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Activated T Cells Induce Macrophages To Produce NO and Control Leishmania major in the Absence of Tumor Necrosis Factor Receptor p55

Infection and Immunity ◽

10.1128/iai.68.3.1428-1434.2000 ◽

2000 ◽

Vol 68 (3) ◽

pp. 1428-1434 ◽

Cited By ~ 23

Author(s):

Michelle Nashleanas ◽

Phillip Scott

Keyword(s):

T Cells ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Leishmania Major ◽

Tumor Necrosis Factor Receptor ◽

No Production ◽

Activated T Cells ◽

Necrosis Factor

ABSTRACT The ability to activate macrophages in vitro for nitric oxide production and killing of Leishmania major parasites is dependent on tumor necrosis factor, although L. major-infected mice lacking the TNF receptor p55 (TNFRp55−/− mice) or both the TNFRp55 and TNFRp75 (TNFRp55p75−/− mice) are able to produce NO in vivo and eliminate the parasites. Here we report that activated T cells cocultured with macrophages results in TNFR-independent activation sufficient to control parasites and that both CD40/CD40L and LFA-1 contribute to T-cell-mediated macrophage activation. Thus, anti-CD3-stimulated T cells activated TNFR-deficient macrophages, while T cells from CD40L−/− mice were partially defective in triggering NO production by TNFRp55p75−/− macrophages. Moreover, in the presence of gamma interferon, anti-CD40 monoclonal antibody (MAb) activated TNFR-deficient macrophages. Finally, MAb blockade of LFA-1 completely inhibited macrophage NO production. Our data indicate that T cells can activate macrophages in the absence of TNF, thus providing a mechanism for how TNFR-deficient mice can control intracellular pathogens.

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N-acetyl-L-cysteine Exhibits Antitumoral Activity by Increasing Tumor Necrosis Factor α-Dependent T-Cell Cytotoxicity

Blood ◽

10.1182/blood.v90.3.1124.1124_1124_1132 ◽

1997 ◽

Vol 90 (3) ◽

pp. 1124-1132

Author(s):

Yves Delneste ◽

Pascale Jeannin ◽

Laurent Potier ◽

Pedro Romero ◽

Jean-Yves Bonnefoy

Keyword(s):

T Cells ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Antitumoral Activity ◽

Lymphoma Cells ◽

Factor Α ◽

Necrosis Factor

Because of its anticarcinogenic and antimutagenic properties, N-acetyl-L-cysteine (NAC) has been proposed for cancer treatment. Here we present a mechanism of action for NAC in cancer. Our data show that NAC (1) induces an early and sustained increase of membrane tumor necrosis factor α (TNFα) expression on human stimulated-peripheral blood (PB) T cells and (2) increases membrane TNF-RI and TNF-RII on tumoral cell lines and on T cells after stimulation. These effects result from an early inhibition of both TNFα and TNF-R shedding, as well as a later increase of the respective mRNA expression. Consequently, NAC confers cytotoxic properties to human PB T cells through a membrane TNFα-dependent pathway. In vivo, NAC given orally inhibits tumor appearance in more than a third (18 out of 50) B6D2F1 mice injected with L1210 lymphoma cells. Spleen cells from protected mice killed L1210 lymphoma cells in vitro in a membrane TNFα-dependent manner. Furthemore these mice were resistant to a second inoculation of L1210 cells without further treatment with NAC. Thus, NAC exhibits a potent antitumoral activity by modulating TNFα and TNF-R processing without showing any in vitro and in vivo toxicity.

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N-acetyl-L-cysteine Exhibits Antitumoral Activity by Increasing Tumor Necrosis Factor α-Dependent T-Cell Cytotoxicity

Blood ◽

10.1182/blood.v90.3.1124 ◽

1997 ◽

Vol 90 (3) ◽

pp. 1124-1132 ◽

Cited By ~ 27

Author(s):

Yves Delneste ◽

Pascale Jeannin ◽

Laurent Potier ◽

Pedro Romero ◽

Jean-Yves Bonnefoy

Keyword(s):

T Cells ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Antitumoral Activity ◽

Lymphoma Cells ◽

Factor Α ◽

Necrosis Factor

Abstract Because of its anticarcinogenic and antimutagenic properties, N-acetyl-L-cysteine (NAC) has been proposed for cancer treatment. Here we present a mechanism of action for NAC in cancer. Our data show that NAC (1) induces an early and sustained increase of membrane tumor necrosis factor α (TNFα) expression on human stimulated-peripheral blood (PB) T cells and (2) increases membrane TNF-RI and TNF-RII on tumoral cell lines and on T cells after stimulation. These effects result from an early inhibition of both TNFα and TNF-R shedding, as well as a later increase of the respective mRNA expression. Consequently, NAC confers cytotoxic properties to human PB T cells through a membrane TNFα-dependent pathway. In vivo, NAC given orally inhibits tumor appearance in more than a third (18 out of 50) B6D2F1 mice injected with L1210 lymphoma cells. Spleen cells from protected mice killed L1210 lymphoma cells in vitro in a membrane TNFα-dependent manner. Furthemore these mice were resistant to a second inoculation of L1210 cells without further treatment with NAC. Thus, NAC exhibits a potent antitumoral activity by modulating TNFα and TNF-R processing without showing any in vitro and in vivo toxicity.

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T Cell Receptor (TCR) Engagement Leads to Activation-induced Splicing of Tumor Necrosis Factor (TNF) Nuclear Pre-mRNA

Journal of Experimental Medicine ◽

10.1084/jem.188.2.247 ◽

1998 ◽

Vol 188 (2) ◽

pp. 247-254 ◽

Cited By ~ 35

Author(s):

Yang Yang ◽

Ju-Fay Chang ◽

Jane R. Parnes ◽

C. Garrison Fathman

Keyword(s):

Gene Expression ◽

T Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

T Cell Receptor ◽

Tumor Necrosis ◽

Protein Production ◽

Cell Receptor ◽

Activated T Cells ◽

Necrosis Factor

Inducible gene expression is primarily regulated at the level of transcription. Additional steps of “processing” pre-mRNA, involved in the regulation of induced gene expression, have not been previously reported. Here we report a novel mechanism of “activation-induced splicing” of preexisting tumor necrosis factor (TNF) message (pre-mRNA) in naive T lymphocytes after engagement of the T cell receptor (TCR), which still occurs after inhibition of transcription. Expression of TNF has been previously demonstrated to be regulated at both the transcriptional and translational levels. However, neither the large pool of TNF mRNA observed in activated T cells nor TNF protein production, which peaks very shortly after activation, can be solely attributed to increased transcription. Evidence is presented that activation-induced splicing of TNF pre-mRNA plays a significant role in the rapid production of TNF seen in activated T cells. Activation triggers processing of TNF pre-mRNA that has accumulated in naive T cells (before activation-induced transcription), and the mature TNF mRNA is translocated to the cytoplasm for rapid translation and protein production. This novel form of activation-induced splicing of TNF may allow T cells to mount an immediate response to activation stimuli under physiological conditions.

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T cell receptor reconstitution fails to restore responses of T cells rendered hyporesponsive by tumor necrosis factor

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0308231100 ◽

2004 ◽

Vol 101 (6) ◽

pp. 1696-1701 ◽

Cited By ~ 18

Author(s):

J. M. Clark ◽

A. E. Annenkov ◽

M. Panesar ◽

P. Isomaki ◽

Y. Chernajovsky ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

T Cell Receptor ◽

Tumor Necrosis ◽

Cell Receptor ◽

Necrosis Factor

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T cell receptor-dependent cell death of T cell hybridomas mediated by the CD30 cytoplasmic domain in association with tumor necrosis factor receptor-associated factors.

Journal of Experimental Medicine ◽

10.1084/jem.183.2.669 ◽

1996 ◽

Vol 183 (2) ◽

pp. 669-674 ◽

Cited By ~ 115

Author(s):

S Y Lee ◽

C G Park ◽

Y Choi

Keyword(s):

Cell Death ◽

T Cell ◽

Tumor Necrosis Factor ◽

T Cell Receptor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Cell Receptor ◽

Cytoplasmic Domain ◽

Activated T Cells ◽

Necrosis Factor

CD30 is a member of the tumor necrosis factor superfamily and a surface marker for Hodgkin's disease. Normal activated T cells and several virally transformed T or B cell lines also show CD30 expression. The interaction of CD30 with its ligand induces cell death or proliferation, depending on the cell type. In this report we characterize the signals mediated by the intracellular domain of CD30 and show that, in combination with signal(s) transduced by the T cell receptor, the multimerization of CD30 cytoplasmic domain induces Fas(CD95)-independent cell death in T cell hybridomas. Deletion analysis shows that the COOH-terminal 66 amino acids of CD30 are required to induce cell death. Using the yeast two-hybrid system, we have identified that the same region of CD30 interacts with tumor necrosis factor receptor-associated factor (TRAF)1 and TRAF2. These results indicate that TRAF1 and/or TRAF2 play an important role in cell death in addition to their previously identified roles in cell proliferation.

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Abstract 354: Lower Circulating Levels of Tumor Necrosis Factor Related Apoptosis-inducing Ligand (TRAIL) are Associated with Increased Sub-clinical Coronary Atherosclerosis among Smokers

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.354 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Aman Gupta ◽

Divay Chandra ◽

Yingze Zhang ◽

Steven Reis ◽

Frank Sciurba

Keyword(s):

Tumor Necrosis Factor ◽

Coronary Atherosclerosis ◽

Tumor Necrosis ◽

Smoking Status ◽

Calcium Score ◽

Meso Scale Discovery ◽

The Mean ◽

Necrosis Factor

Rationale: There is significant in vitro evidence demonstrating anti-atherogenic effect of circulating Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Also, decreased circulating TRAIL levels have been reported in patients with acute myocardial infarction and in those undergoing coronary catheterization due to suspected coronary atherosclerosis. However, it remains unknown if TRAIL levels are associated with sub-clinical coronary atherosclerosis. Methods: The study included 460 current and former smokers enrolled in the Pittsburgh COPD SCCOR study. Serum TRAIL levels were measured by electrochemiluminescence immunoassay, according to the manufacture’s protocol (Meso Scale Discovery, Gaithersburg, Maryland). Coronary atherosclerosis was assessed by a validated visual coronary artery calcium scoring system using non-EKG gated chest CT scans (Weston score). Ordinal logistic regression models were used to identify significant associations between categories of CAC score (0, 1-3, 4-8, and 9-12) and TRAIL level, and to adjust for cardiovascular risk factors. Results: The mean age of the 460 participants was 65.7 ± 6.3 years, 52.2% were male, and the mean pack years of smoking was 55.0 ± 30.8 years. In univariate analyses, each standard deviation decrease in TRAIL levels was associated with 1.42-fold increase in the odds of having calcium scores in one higher category (p<0.001). This association persisted despite adjustment for age, gender, race, body mass index, hypertension, diabetes, hyperlipidemia, pack years of smoking, and current smoking status (adjusted OR for higher category of calcium score per SD decrease in TRAIL level 1.22, p=0.04). Conclusions: Our results expand on the in vitro and in vivo data linking decreased TRAIL levels with increased atherosclerosis by demonstrating a novel association between lower circulating TRAIL and increased subclinical coronary atherosclerosis.

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