Expression and functional significance of an additional ligand for CTLA-4.

Lenschow, Deborah J.; Su, Gloria H.; Zuckerman, L; Nabavi, Nasrin; Jellis, Cindy L.; Gray, Gary S.; Miller, Jim; Bluestone, Jeffrey A.

doi:10.1073/pnas.90.23.11054

Cited by 226 publications

(157 citation statements)

References 33 publications

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“…In addition, full activation of these cells requires the binding of costimulatory molecules expressed on one cell to costimulatory molecules expressed on the other (3,4). One such costimulatory molecule is CD86 (B7-2), which is expressed at a low level on a resting B cell (5,6), but is up-regulated following the stimulation of BCR (7,8), CD40 (9,10), MHC class II (11), LPS receptor (5,7,12,13), IL-4R (14,15), and/or ␤ 2 -adrenergic receptor (␤ 2 AR) (16,17). CD86 binds to the costimulatory molecule CD28 on the Th cell to increase the expression of the costimulatory molecule CD40 ligand (CD40L) on the Th cell and also to increase the level of cytokine produced by the Th cell (13,15,18).…”

Section: Selective Regulation Of Mature Igg1 Transcription By Cd86mentioning

confidence: 99%

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

Podojil

Sanders

2003

The Journal of Immunology

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Stimulation of CD86 and the β2-adrenergic receptor (β2AR) on a B cell, either alone or together, is known to increase the level of IgG1 protein produced by a CD40 ligand/IL-4-activated B cell. It is also known that the mechanism by which CD40 and IL-4R stimulation on a B cell increases the level of IgG1 protein is by increasing germline γ1 transcription, IgG1 class switching, and mature IgG1 transcription, while the molecular mechanism responsible for mediating the CD86- and β2AR-induced effect remains unknown. In the present study using real-time PCR we show that the level of mature IgG1 transcription increases in CD40 ligand/IL-4-activated B cells following stimulation of either CD86 and/or β2AR, and that this increase reflects the increase in IgG1 protein. Furthermore, we show that the CD86- and/or β2AR-induced increase in mature IgG1 transcript is due to an increase in the rate of mature IgG1 transcription, as determined by nuclear run-on analysis. This effect is additive when both receptors are stimulated and is lost when B cells from CD86- and β2AR-deficient mice are used. In contrast, the level of germline γ1 transcription, the stability of mature IgG1 transcript, the number of IgG1-positive B cells, and the number of IgG1-secreting B cells did not change. These results provide the first evidence that CD86 and/or β2AR stimulation on a CD40 ligand/IL-4-activated B cell increases the level of IgG1 protein produced per cell by increasing the rate of mature IgG1 transcription.

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Section: Selective Regulation Of Mature Igg1 Transcription By Cd86mentioning

confidence: 99%

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

Podojil

Sanders

2003

The Journal of Immunology

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“…Opposite expression patterns of these costimulatory molecules were observed following L-PAM therapy of MOPC-315 tumor bearers (15). Specifically, B7-1 was up-regulated at the tumor site within 24 h after L-PAM treatment (15), whereas B7-2 was up-regulated after 48 h (11), which is similar to the time of up-regulation of B7-2 expression on APC exposed to the other stimuli (12)(13)(14). In light of these observations, we considered the possibility that in contrast to B7-2, which is up-regulated indirectly by L-PAM (i.e., L-PAM induces TNF-␣ production (16) that in turn leads to up-regulation of B7-2 surface expression; Ref.…”

Section: Mechanism Of Melphalanmentioning

confidence: 73%

“…Numerous investigators observed that B7-2 expression was upregulated earlier than B7-1 following stimulation of APCs with a variety of different stimuli including cytokines (e.g., GM-CSF), anti-CD40, or surface Ig ligation (12)(13)(14). Opposite expression patterns of these costimulatory molecules were observed following L-PAM therapy of MOPC-315 tumor bearers (15).…”

Section: Mechanism Of Melphalanmentioning

confidence: 99%

Mechanism of Melphalan-Induced B7-1 Gene Expression in P815 Tumor Cells

Donepudi

Raychaudhuri

Bluestone

et al. 2001

The Journal of Immunology

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We have previously shown that exposure of P815 tumor cells to melphalan (l-phenylalanine mustard; l-PAM) leads to up-regulation of B7-1 surface expression, and this l-PAM-induced up-regulation requires de novo RNA synthesis and is associated with accumulation of B7-1 mRNA. Here we show that the effect of l-PAM on B7-1 surface expression can be mimicked by exposing P815 tumor cells to oxidative stress but not to heat shock. Moreover, the antioxidant N-acetyl-l-cysteine prevented the l-PAM-induced accumulation of B7-1 mRNA in P815 tumor cells, suggesting that reactive oxygen species are involved in the transcriptional regulation of l-PAM-induced B7-1 gene expression. Although AP-1 and NF-κB are regarded as redox-sensitive transcription factors and the promoter/enhancer region of the B7-1 gene contains an AP-1 and an NF-κB binding site, exposure of P815 tumor cells to l-PAM led to rapid and transient activation only of NF-κB, but not AP-1, that bound specifically to a probe containing the respective binding site in the murine or human B7-1 gene. Moreover, exposure of P815 tumor cells to a cell-permeable peptide that selectively inhibits NF-κB activation by blocking the activation of the IκB-kinase complex was found to inhibit the l-PAM-induced B7-1 mRNA accumulation, indicating that NF-κB activation is essential for the l-PAM-induced B7-1 gene expression. Taken together, these results indicate that l-PAM leads to activation of B7-1 gene expression by activating NF-κB via a pathway that involves reactive oxygen species.

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“…It is reported that both B7-1 and B7-2 are the ligands for CTLA4 and expressed on cell surface as membrane antigens [8][9][10][11]. CTLA4Ig binds these molecules with very high affinity [1].…”

Section: Ctla4ig From Transfected Mm1 Cells Binds Effectively To B7 Mmentioning

confidence: 99%

“…B7 molecules are expressed on a variety of cell types, including dentritic cells, B cells, T-cells and macrophages [8][9][10][11]. CTLA4Ig, a soluble form of CTLA4, could block B7 and CD28/CTLA4 pathway and results in the inhibitation of Tcell activation and autoimmune response [12][13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Expression of a soluble form of CTLA4 on macrophage and its biological activity

et al. 1999

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Interaction between cytotoxic T lymphocyte-asso-ciated antigen-4 (CTLA4, CD152) and B7 molecules (B7-1 and B7-2) is of importance in the cellular events of lymphocyte, including antigen-specific T-cell activation and induction of autoreactive T-cell. We describe here the first introduction of a murine soluble CTLA4 gene, CTLA4Ig, to Mm1 cells, a macrophagic cell line. CTLA4Ig was successfully expressed on Mm1 cells and the expressed CTLA4Ig was found to be functionally active in their binding to B7 molecules by flow cytometry and immunofl-uorescence studies. The biological activity of CTLA4Ig from the transfected Mm1 cells was studied and showed inhibitory activity on mixed lymphocyte culture. A high CTLA4Ig producing macrophagic cell line was obtained. As Mm1 cells were regarded as difficult for gene transfection and there had so far been no report on expression of CTLA4Ig gene on Mm1 cells, these results suggested that the CTLA4Ig ex- 190Expression of CTLA4 on Mm1 and its biological activity pressing Mm1 cells could be useful for analysis of CTLA4 and B7 molecule interaction in both macrophage and T-cell.

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Expression and functional significance of an additional ligand for CTLA-4.

Abstract: Effective T-cell activation requires antigen/major histocompatibility complex engagement by the

Cited by 226 publications

References 33 publications

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

Mechanism of Melphalan-Induced B7-1 Gene Expression in P815 Tumor Cells

Expression of a soluble form of CTLA4 on macrophage and its biological activity

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