A signaling pathway coupled to T cell receptor ligation by MMTV superantigen leading to transient activation and programmed cell death

Weber, Georg F.; Abromson‐Leeman, Sara; Cantor, Harvey

doi:10.1016/1074-7613(95)90144-2

Cited by 36 publications

(31 citation statements)

References 45 publications

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“…We postulate that once the conditions for suppression have been established in vivo, subsequent antigenic restimulation in vitro promotes further IFN-␥ production, stimulating small numbers of Gr-1 ϩ cells in the enriched T cell cultures to produce a combination of RNI and ROI. Our data suggest that RNI and ROI directly cause activated or responding CD4 T cells to undergo apoptosis, as has been suggested in other models (20,21,33,34). This possibility will be further investigated in future studies.…”

Section: Discussionsupporting

confidence: 61%

“…More recently, a mimetic of SOD was used to show that low doses of injected SEA can induce a superoxidemediated mechanism of cell death in T cells from SAg-treated mice (21). This study did not show in vivo data; however, an earlier study showed that NAC slightly enhanced T cell survival in mice stimulated with a mouse mammary tumor virus-derived SAg (20). The origin of the ROI was not investigated in either of these studies.…”

Section: Discussionmentioning

confidence: 51%

“…IFN-␥ and NO production also prevent activated CD4 T cells from accumulating in mice infected with bacillus Calmette-Guérin (BCG) bacteria (18) or lymphocytic choriomeningitis virus (19). In other studies, reactive oxygen intermediates (ROI) were suggested to play a role in regulating T cell survival in SAg-treated mice (20,21). Together, these reports suggest that reactive molecules, which can be produced by myeloid cells, may play an important role in down-regulating T cell responses in vivo.…”

Section: S Uperantigens (Sag)mentioning

confidence: 67%

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Superantigen-Induced CD4 T Cell Tolerance Mediated by Myeloid Cells and IFN-γ

Cauley

Miller

Yen

et al. 2000

The Journal of Immunology

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We have previously shown that systemic staphylococcal enterotoxin A (SEA) injections cause CD4 T cells in TCR-transgenic mice to become tolerant to subsequent ex vivo restimulation. An active IFN-γ-dependent mechanism of suppression was responsible for the apparent unresponsiveness of the CD4 T cells. In this study, we analyze the response of CD4 T cells isolated throughout the first 10 days of the in vivo response to injected SEA. We show that CD4 T cells isolated at the peak of the in vivo response undergo very little activation-induced cell death after sterile FACS sorting or restimulation in the presence of neutralizing Abs to IFN-γ. We also show that the IFN-γ-dependent tolerance develops soon after SEA injection in the spleens of both normal and TCR-transgenic mice. This suppression is dependent upon myeloid cells from the SEA-treated mice and is optimal when inducible NO synthase activity and reactive oxygen intermediates are both present. The data indicate that IFN-γ, myeloid cells, and a combination of NO and reactive oxygen intermediates all contribute to a common pathway of T cell death that targets activated or responding CD4 T cells. Sorted Gr-1+ cells from SEA-treated mice also directly suppress the response of naive CD4 T cells in mixed cultures, indicating that this tolerance mechanism may play a role in down-regulating other vigorous immune responses.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 51%

Section: S Uperantigens (Sag)mentioning

confidence: 67%

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Superantigen-Induced CD4 T Cell Tolerance Mediated by Myeloid Cells and IFN-γ

Cauley

Miller

Yen

et al. 2000

The Journal of Immunology

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“…The induction of various oxidoreductase genes by osteopontin, found in the microarray analysis, is consistent with these functions. Apoptosis frequently involves the generation of and signal transduction by free radicals (Weber et al, 1995). Anchorage independence in soft agar largely reflects resistance to a form of apoptosis referred to as anoikis.…”

Section: Discussionmentioning

confidence: 99%

An osteopontin splice variant induces anchorage independence in human breast cancer cells

2005

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In malignant tumors, metastasis genes are typically deregulated by aberrant expression or splicing. Osteopontin is expressed at high levels by various cancers and contributes importantly to their invasive potential. In contrast, osteopontin derived from host cells induces cellular immunity and could bolster antitumor protection by cytotoxic T lymphocytes. Here we show that breast cancer cells express multiple splice variants of osteopontin. According to RT-PCR analysis of human breast tissue specimens, the splice variant osteopontin-c is a highly specific marker for transformed cells, which is not expressed in their surrounding normal tissue. The fulllength form of osteopontin aggregates in the presence of physiologic amounts of calcium and, in this state, leads to enhanced cell adhesion. Ostensibly, this effect is inhibitory for tumor cell dissemination. The shortest splice variant, osteopontin-c, does not aggregate in the presence of calcium and enhances clone formation in soft agar. According to microarray analysis, osteopontin-c induces the expression of oxidoreductases, consistent with protection from anoikis during anchorage-independent growth. These studies define a third functional domain of osteopontin, beside the C-terminal CD44-binding site and the central integrin-binding site. They also provide evidence for a bifunctional character of osteopontin, with the soluble form supporting invasiveness and the aggregated form promoting adhesion.

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“…It has been shown that ROS play a pivotal role in numerous signaling pathways in physiologic and pathophysiologic settings. In T cells, several studies have suggested that T cell activation stimulates ROS generation (5)(6)(7).…”

mentioning

confidence: 99%

Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production

Monick

Samavati

Butler

et al. 2003

The Journal of Immunology

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A number of lung diseases, including many interstitial lung diseases and HIV infection, are associated with decreases in intracellular thiols. Altered Th1/Th2 T cell balance has also been associated with disease progression in many of the same diseases. IFN-γ and IL-4 are critical effector cytokines of Th1 and Th2 cells, respectively. To determine the effect of thiols on the production of IFN-γ and IL-4 by splenocytes, cells were incubated in the presence and the absence of N-acetylcysteine (NAC) and stimulated with αCD3 or αCD3 and IL-12. Augmenting intracellular soluble thiol pools (∼2-fold) with 15 mM NAC blocked induction of IFN-γ and increased production of IL-4 without causing significant changes in intracellular glutathione levels. The effect of NAC on IL-4 production was not linked to an increase in STAT6 phosphorylation, as STAT6 levels were decreased, nor did the increase in IL-4 occur with purified CD4 cells. We found that NAC increased splenocyte IL-4 production via an effect on APCs. We also found that NAC increased two IL-4 relevant transcription factors (AP-1) and NFATc. These studies suggest that increasing intracellular reduced thiol pools decreases IL-12 signaling and IFN-γ production, while increasing IL-4 production. The sum of these effects may contribute to alterations in the balance between Th1 and Th2 responses in lung diseases associated alterations in intracellular thiol pools.

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A signaling pathway coupled to T cell receptor ligation by MMTV superantigen leading to transient activation and programmed cell death

Cited by 36 publications

References 45 publications

Superantigen-Induced CD4 T Cell Tolerance Mediated by Myeloid Cells and IFN-γ

Superantigen-Induced CD4 T Cell Tolerance Mediated by Myeloid Cells and IFN-γ

An osteopontin splice variant induces anchorage independence in human breast cancer cells

Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production

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