Proteins Antigenically Related to Peptides Encoded by the Mouse Mammary Tumour Virus Long Terminal Repeat Sequence Are Associated with Intracytoplasmic A Particles

Smith, Gilbert H.; Young, Lawrence J.T.; Benjamini, E.; Medina, Daniel; Cardiff, Robert D.

doi:10.1099/0022-1317-68-2-473

Cited by 10 publications

(3 citation statements)

References 29 publications

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“…We show here that B cells are the primary target for MMTV infection since ORF transcripts and the bulk of reversetranscribed viral genome are present in B cells. Since we show that the mature virus particle does not contain ORF transcripts and it is believed that ORF protein is not present in the mature virion (35), it is likely that after infection, de novo ORF protein expression and presentation in the context of MHC class II antigens (36) by infected B cells leads to stimulation of ORF-reactive CD4 + T cells. B cells are then stimulated by these activated CD4 + T cells.…”

Section: Discussionmentioning

confidence: 96%

Superantigen-reactive CD4+ T cells are required to stimulate B cells after infection with mouse mammary tumor virus.

Held

Shakhov

Izui

et al. 1993

The Journal of Experimental Medicine

132

125

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SummarySuperantigens are defined by their ability to stimulate a large fraction of T cells via interaction with the T cell receptor (TCR) V/3 domain. Endogenous superantigens, classically termed minor lymphocyte-stimulating (Mls) antigens, were recently identified as products of open reading flames (ORF) in integrated proviral copies of mouse mammary tumor virus (MMTV). We have described an infectious MMTV homologue of the classical endogenous superantigen Mls-1 ~ (Mtv-7). The ORF molecules of both the endogenous Mtv-7 and the infectious MMTV(SW) interact with T cells expressing the TCR VB6, 7, 8.1, and 9 domains. Furthermore, the COOH termini of their ORF molecules, thought to confer TCR specificity, are very similar. Since successful transport of MMTV from the site of infection in the gut to the mammary gland depends on a functional immune system, we were interested in determining the early events after and requirements for MMTV infection. We show that MMTV(SW) infection induces a massive response of V~6 + CD4 + T cells, which interact with the viral ORE Concomitantly, we observed a B cell response and differentiation that depends on both the presence and stimulation of the superantigen-reactive T cells. Furthermore, we show that B cells are the main target of the initial MMTV infection as judged by the presence of the reverse-transcribed viral genome and ORF transcripts. Thus, we suggest that MMTV infection of B cells leads to ORF-mediated B-T cell interaction, which maintains and possibly amplifies viral infection. M inor lymphocyte-stimulating (Mls) antigens are encodedby an open reading frame (ORF) z in the 3' LTR of endogenous mouse mammary tumor virus (MMTV) (1-3). They stimulate a large proportion of T cells due to the fact that T cell reactivity to Mls antigens is determined by the usage of the V segment of the TCR B chain (4, 5). The classical (and strongest) Mls determinant, Mls-1 ', which interacts with T cells expressing VB6, 7, 8.1, and 9 elements (4-7), is encoded by the ORF of the Mtv-7 proviral locus (8). We have recently found an exogenous (infectious) MMTV, MMTV(SW), with properties of Mls-1 ' (9). The ORF molecules of Mtv-7 and MMTV(SW) display an almost identical amino acid sequence, particularly in COOH termini implied to confer TCR VB specificity. In fact, both endogenous Mtv-7 and infectious MMTV(SW) interact with the same TCR VB elements. In an MMTV-infected host, ORF-reactive T cells are deleted from both the thymic and peripheral T cell pool, although at a considerably slower rate than after expression of the endogenous Mtv-7 (Mls-l') locus. Furthermore, injection of adult mice with MMTV(SW) leads to expansion of V~6 + CD4 + T cells similar to that observed after injection of . A functional immune system seems to be a prerequisite for successful transport of MMTV to the mammary gland after neonatal infection through the gut mucosa. Thus, thymectomy, absence of T cells (in nude mice), or deletion of the ORF-reactive T cells prevent virus transmission to the next generation (lO-12).Whil...

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Section: Discussionmentioning

confidence: 96%

Superantigen-reactive CD4+ T cells are required to stimulate B cells after infection with mouse mammary tumor virus.

Held

Shakhov

Izui

et al. 1993

The Journal of Experimental Medicine

132

125

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“…The biological significance of the orf coding sequence in the LTR region is still unclear. Perhaps if the orf protein is necessary for biological function, as suggested by Smith et al (43), then in T cells the N-terminal portion is sufficient.…”

Section: Discussionmentioning

confidence: 97%

Alterations in the U3 region of the long terminal repeat of an infectious thymotropic type B retrovirus

Ball

Diggelmann

Dekaban

et al. 1988

J Virol

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We isolated and characterized a type B thymotropic retrovirus (DMBA-LV) which is highly related to mouse mammary tumor virus (MMTV) isolates and which induces T-cell thymomas with a high incidence and a very short latent period. Regions of nonhomology between the DMBA-LV genome and the MMTV genome were identified by heteroduplex mapping and nucleotide sequence studies. In the electron microscope heteroduplex mapping studies the EcoRIgenerated 5' and 3' fragments of the DMBA-LV genome were compared with the corresponding fragments of the MMTV (C3H and GR) genome isolated from mammary tumors. The results indicated that DMBA-LV contained a region of nonhomologous nucleotide sequences in the 3' half of the U3 region of the long terminal repeat (LTR). Nucleotide sequence studies confirmed these results and showed that in this region 440 nucleotides of the MMTV (C3H) sequences were deleted and substituted with a segment of 122 nucleotides. This substituted segment in the form of a tandem repeat structure contained nucleotide sequences derived exclusively from sequences which flanked the substitution loop. The distal glucocorticoid regulatory element was unaltered, and two additional copies of the distal glucocorticoid regulatory elementbinding site were present in the substituted region. The restriction endonuclease map of the reconstructed molecular clone of DMBA-LV was identical to that corresponding to unintegrated linear DMBA-LV DNA present in DMBA-LV-induced tumor cell lines. Since the nucleotide sequences of the LTRs present in four different DMBA-LV proviral copies isolated from a single thymoma were identical, we concluded that they were derived from the same parental virus and that this type B retrovirus containing an alteration in the U3 region of its LTR could induce thymic lymphomas. Thus, DMBA-LV represents the first example of a productively replicating type B retrovirus that contains an LTR modified in the U3 region and that has target cell and disease specificity for T cells.

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“…B cells were used as an example to illustrate the details of SAg presentation. The mature MMTV virion did not contain SAg transcripts and protein ( Smith et al., 1987 ; Held et al., 1993 ). B cells express SAg via the regulation of proviral transcriptional enhancers.…”

Section: Mmtv-infected Apcs Present Sag By Mhcii Moleculementioning

confidence: 99%

Intestinal Immune System and Amplification of Mouse Mammary Tumor Virus

Chen

Liu

Chen

et al. 2022

Front. Cell. Infect. Microbiol.

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Mouse mammary tumor virus (MMTV) is a virus that induces breast cancer in mice. During lactation, MMTV can transmit from mother to offspring through milk, and Peyer’s patches (PPs) in mouse intestine are the first and specific target organ. MMTV can be transported into PPs by microfold cells and then activate antigen-presenting cells (APCs) by directly binding with Toll-like receptors (TLRs) whereas infect them through mouse transferrin receptor 1 (mTfR1). After being endocytosed, MMTV is reversely transcribed and the cDNA inserts into the host genome. Superantigen (SAg) expressed by provirus is presented by APCs to cognate CD4+ T cells via MHCII molecules to induce SAg response, which leads to substantial proliferation and recruitment of related immune cells. Both APCs and T cells can be infected by MMTV and these extensively proliferated lymphocytes and recruited dendritic cells act as hotbeds for viral replication and amplification. In this case, intestinal lymphatic tissues can actually become the source of infection for the transmission of MMTV in vivo, which results in mammary gland infection by MMTV and eventually lead to the occurrence of breast cancer.

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Proteins Antigenically Related to Peptides Encoded by the Mouse Mammary Tumour Virus Long Terminal Repeat Sequence Are Associated with Intracytoplasmic A Particles

Cited by 10 publications

References 29 publications

Superantigen-reactive CD4+ T cells are required to stimulate B cells after infection with mouse mammary tumor virus.

Superantigen-reactive CD4+ T cells are required to stimulate B cells after infection with mouse mammary tumor virus.

Alterations in the U3 region of the long terminal repeat of an infectious thymotropic type B retrovirus

Intestinal Immune System and Amplification of Mouse Mammary Tumor Virus

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