META-Controlled env-Initiated Transcripts Encoding Superantigens of Murine Mtv29 and Mtv7 and Their Possible Role in B Cell Lymphomagenesis

Sen, Namita; Simmons, William J.; Thomas, Robin; Erianne, Gregory S; Zhang, Dajun; Jaeggli, Nelson S.; Huang, Chengcheng; Xiong, Xiaozhong; Tsiagbe, V. K.; Ponzio, Nicholas M.; Thorbecke, G. J.

doi:10.4049/jimmunol.166.9.5422

Cited by 15 publications

(10 citation statements)

References 43 publications

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“…tumor cells express a vSAg encoded by an endogenous retrovirus, one would expect that the tumor-specific Th cells would express the same TCR V␤ (13). All Th cell lines were restricted with respect to their V␤-chains; the predominant chain was V␤16 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Due to recognition of mouse mammary tumor virus-encoded vSAg in SJL lymphoma cells, there is skewing of TCR V␤ chains expressed on responding SJL T cells (13,25). Therefore, we determined whether the TCR V␤-chains of the tumor-responsive Th cell lines were skewed toward a particular V␤.…”

Section: Characterization Of Th Cell Linesmentioning

confidence: 99%

“…Tissues harvested from mice were immediately fixed in Telly's or formalin fixative and embedded, then sectioned and stained as previously described (13).…”

Section: Detection Of Primary Rcs Development In Vivomentioning

confidence: 99%

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Tim-3+ T-bet+ Tumor-Specific Th1 Cells Colocalize with and Inhibit Development and Growth of Murine Neoplasms

Simmons

Koneru

Mohindru

et al. 2005

The Journal of Immunology

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Although T cells infiltrate many types of murine and human neoplasms, in many instances tumor-specific cytotoxicity is not observed. Strategies to stimulate CTL-mediated antitumor immunity have included in vitro stimulation and/or genetic engineering of T cells, followed by adoptive transfer into tumor-bearing hosts. In this model of B cell lymphoma in SJL/J mice, we used Tim-3+ T-bet+ Th1 cells to facilitate the development of tumor-specific CTL. Tumor-specific Th1 cell lines were polarized with IL-12 during in vitro stimulation and long term maintenance. As few as 5 million Tim-3+ T-bet+ Th1 cells enabled recipients to resist growth of malignant transplantable cells. In addition, similar numbers of Th1 cells injected into 2- to 3-mo-old mice inhibited development of the spontaneous primary lymphomas, which normally arise in 90% of aging mice. CFSE+ Th1 cells colocalized with injected tumor cells in vivo and formed conjugates with the tumor cells within follicles, whereas in nontumor-challenged recipients the CFSE+ Th1 cells localized only within the T cell zones of the spleen. These results provide evidence that adoptive immunotherapy with Tim-3+ T-bet+ tumor-specific Th1 cells can be used to induce host cytotoxic responses that inhibit the development and growth of neoplastic cells.

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Section: Discussionmentioning

confidence: 99%

Section: Characterization Of Th Cell Linesmentioning

confidence: 99%

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Tim-3+ T-bet+ Tumor-Specific Th1 Cells Colocalize with and Inhibit Development and Growth of Murine Neoplasms

Simmons

Koneru

Mohindru

et al. 2005

The Journal of Immunology

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“…If indeed such infection of human B and T cells can occur this may allow not only for the passage of MMTV to the breast as in the mouse but also to function as an etiological agent of disease in the lymphoid tissue itself. Spontaneous lymphomas arise in Ͼ90% of SJL mice by the age of 12 months and are of B-cell origin (58). The cells of these lymphomas stimulate T cells via expression of endogenous MMTV sag, and the cytokines produced by these activated T cells promote growth of the lymphomas.…”

Section: Discussionmentioning

confidence: 99%

Clonal Isolation of Different Strains of Mouse Mammary Tumor Virus-Like DNA Sequences from Both the Breast Tumors and Non-Hodgkin’s Lymphomas of Individual Patients Diagnosed with Both Malignancies

Etkind

Stewart

Dorai

et al. 2004

Clinical Cancer Research

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Purpose: In a previous study, we had detected the presence of mouse mammary tumor virus (MMTV)-like envelope (ENV) gene sequences in both the breast tumors and non-Hodgkin's lymphoma tissue of two of our breast tumor patients who had been diagnosed simultaneously with both malignancies. The aim of this study was to determine if MMTV-like DNA sequences are present in the breast tumors and non-Hodgkin's lymphomas of additional patients suffering from both malignancies and if so to characterize these sequences in detail.Experimental Design: DNA was extracted from formalinfixed, paraffin-embedded tissue sample blocks of breast tumors and non-Hodgkin's lymphomas from patients suffering from both malignancies. A 250-bp region of the MMTV ENV gene and a 630-bp region of the MMTV long terminal repeat (LTR) open reading frame (ORF) that encodes the MMTV superantigen (sag) gene were amplified by PCR from the isolated DNA. Amplified products were analyzed by Southern blotting, cloned, and sequenced.Results: MMTV-like ENV and LTR sequences were detected in both the breast tumors and non-Hodgkin's lymphomas of 6 of 12 patients suffering from both malignancies. A novel mutant of the MMTV ENV gene was identified in these patients. Characterization of the MMTV-like LTR highly variable sag sequences revealed total or nearly total identity to three distinct MMTV proviruses from two different branches of the MMTV phylogenetic tree.Conclusions: The presence of MMTV-like ENV and LTR sequences in both the breast tumors and nonHodgkin's lymphomas of 6 additional patients suggests a possible involvement of these sequences in these two malignancies. MMTV-like LTR sequence homology to different MMTV proviruses revealed the presence of more than one strain of MMTV-like sequences in each individual suggesting the possibility of multiple infections in these patients.

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“…B cell lymphomas of SJL/J mice depend for their growth on help from CD4 ϩ V␤16 ϩ T cells, which they stimulate by expressing an Mtv29-encoded proviral superantigen (vSAg29) (1,4). Unlike most other strains of MMTVs, which use promoter elements in the 5Ј LTR for superantigen transcription, the Mtv29 employs a promoter, META, in the env gene for the transcriptional initiation of mRNA encoding vSAg29 (2).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Mouse Mammary Tumor VirusenvTranscriptional Activator Initiated Mammary Tumor Virus Superantigen Transcripts in Lymphomas of SJL/J Mice: Role of Ikaros, Demethylation, and Chromatin Structural Change in the Transcriptional Activation of Mammary Tumor Virus Superantigen

Thomas

Haleem

Siddique

et al. 2003

The Journal of Immunology

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Mammary tumor virus (Mtv29)-encoded superantigen expressed by SJL/J mouse B cell lymphomas stimulates CD4+Vβ16+ T cells and thereby acquires T cell help necessary for lymphoma growth. Mtv29 mouse mammary tumor virus env transcriptional activator (META) env-controlled Mtv29 superantigen (vSAg29) mRNA transcripts (1.8 kb) are not expressed in normal B or other somatic cells. Real-time PCR-based assays with DNA from normal SJL liver and vSAg29− lymphoma (cNJ101), digested with methylation-sensitive enzymes, showed hypermethylation at AvaI, FspI, HpaII, ThaI, and the distal HgaI sites of the META env, but vSAg29+ lymphoma cells showed significant demethylation at AvaI, HpaII, and the distal HgaI sites. The distal HgaI site that is adjacent to an Ikaros binding site is significantly demethylated in the META env DNA from primary lymphomas. Gel shift assays showed binding of Ikaros to a sequence representing this region in the META env. SJL lymphomas expressed the Ikaros isoform Ik6 that was absent in normal B cells. vSAg29+ cells exhibited increased DNaseI accessibility to chromatin at the vSAg29 initiation site. Treatment of cNJ101 cells with a demethylating agent, 5-azacytidine, and a histone deacetylase inhibitor, trichostatin A, caused hypomethylation at AvaI, HpaII, and distal HgaI sites and led to chromatin structural change at the vSAg29 initiation site, accompanied by the expression of vSAg29 transcripts. This enabled cNJ101 cells to stimulate SJL lymphoma-responsive CD4+Vβ16+ T hybridoma cells. Thus, demethylation at the distal HgaI site of the Mtv29 META env permits vSAg29 expression, which may have an impact on the development of germinal center-derived B cell lymphomas of SJL/J mice.

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META-Controlled env-Initiated Transcripts Encoding Superantigens of Murine Mtv29 and Mtv7 and Their Possible Role in B Cell Lymphomagenesis

Cited by 15 publications

References 43 publications

Tim-3+ T-bet+ Tumor-Specific Th1 Cells Colocalize with and Inhibit Development and Growth of Murine Neoplasms

Tim-3+ T-bet+ Tumor-Specific Th1 Cells Colocalize with and Inhibit Development and Growth of Murine Neoplasms

Clonal Isolation of Different Strains of Mouse Mammary Tumor Virus-Like DNA Sequences from Both the Breast Tumors and Non-Hodgkin’s Lymphomas of Individual Patients Diagnosed with Both Malignancies

Regulation of Mouse Mammary Tumor VirusenvTranscriptional Activator Initiated Mammary Tumor Virus Superantigen Transcripts in Lymphomas of SJL/J Mice: Role of Ikaros, Demethylation, and Chromatin Structural Change in the Transcriptional Activation of Mammary Tumor Virus Superantigen

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