scholarly journals Mutational and Functional Analysis of the C-Terminal Region of the C3H Mouse Mammary Tumor Virus Superantigen

1998 ◽  
Vol 72 (6) ◽  
pp. 4746-4755 ◽  
Author(s):  
Thomas J. Wrona ◽  
Mary Lozano ◽  
Awadh A. Binhazim ◽  
Jaquelin P. Dudley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mammary Tumor ◽  
Mouse Mammary Tumor Virus ◽  
Mammary Glands ◽  
Terminal Region ◽  
Target Tissue ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Tumor Virus

ABSTRACT The mouse mammary tumor virus (MMTV) encodes within the U3 region of the long terminal repeat (LTR) a protein known as the superantigen (Sag). Sag is needed for the efficient transmission of milk-borne virus from the gut to target tissue in the mammary gland. MMTV-infected B cells in the gut express Sag as a type II transmembrane protein that is recognized by the variable region of particular beta chains (Vβ) of the T-cell receptor (TCR) on the surface of T cells. Recognition of Sag by particular TCRs results in T-cell stimulation, release of cytokines, and amplification of MMTV infection in lymphoid cells that are needed for infection of adolescent mammary tissue. Because the C-terminal 30 to 40 amino acids of Sag are variable and correlate with recognition of particular TCR Vβ chains, we prepared a series of C-terminal Sag mutations that were introduced into a cloned infectious MMTV provirus. Virus-producing XC rat cells were used for injection of susceptible BALB/c mice, and these mice were monitored for functional Sag activity by the deletion of C3H MMTV Sag-reactive (CD4+Vβ14+) T cells. Injected mice also were analyzed for mutant infection and tumor formation in mammary glands as well as milk-borne transmission of MMTV to offspring. Most mutations abrogated Sag function, although one mutation (HPA242) that changed the negative charge of the extreme C terminus to a positive charge created a weaker Sag that slowed the kinetics of Sag-mediated T-cell deletion. Despite the lack of Sag activity, many of the sag mutant viruses were capable of sporadic infections of the mammary glands of injected mice but not of offspring mice, indicating that functional Sag increases the probability of milk-borne MMTV infection. Furthermore, although most viruses encoding nonfunctional Sags were unable to cause mammary tumors, tumors were induced by such viruses carrying mutations in a negative regulatory element that overlaps the sag gene within the LTR, suggesting that loss of Sag function may be compensated, at least partially, by loss of transcriptional suppression in certain tissues. Together these results confirm the importance of Sag for efficient milk-borne transmission and indicate that the entire C-terminal region is needed for complete Sag function.

scholarly journals Peripheral T cell activation and deletion induced by transfer of lymphocyte subsets expressing endogenous or exogenous mouse mammary tumor virus.

1993 ◽  
Vol 177 (5) ◽  
pp. 1359-1366 ◽  
Author(s):  
G A Waanders ◽  
A N Shakhov ◽  
W Held ◽  
O Karapetian ◽  
H Acha-Orbea ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mammary Tumor ◽  
Mouse Mammary Tumor Virus ◽  
Lymphocyte Subsets ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Tumor Virus ◽  
Cell Deletion

Murine T cell reactivity with products of the minor lymphocyte stimulatory (Mls) locus correlates with the expression of particular variable (V) domains of the T cell receptor (TCR) beta chain. It was recently demonstrated that Mls antigens are encoded by an open reading frame (ORF) in the 3' long terminal repeat of either endogenous or exogenous mouse mammary tumor virus (MMTV). Immature thymocytes expressing reactive TCR-V beta domains are clonally deleted upon exposure to endogenous Mtv's. Mature T cells proliferate vigorously in response to Mls-1a (Mtv-7) in vivo, but induction of specific anergy and deletion after exposure to Mtv-7-expressing cells in the periphery has also been described. We show here that B cells and CD8+ (but not CD4+) T cells from Mtv-7+ mice efficiently induce peripheral deletion of reactive T cells upon transfer to Mtv-7- recipients, whereas only B cells stimulate specific T cell proliferation in vivo. In contrast to endogenous Mtv-7, transfer of B, CD4+, or CD8+ lymphocyte subsets from mice maternally infected with MMTV(SW), an infectious homologue of Mtv-7, results in specific T cell deletion in the absence of a detectable proliferative response. Finally, we show by secondary transfers of infected cells that exogenous MMTV(SW) is transmitted multidirectionally between lymphocyte subsets and ultimately to the mammary gland. Collectively our data demonstrate heterogeneity in the expression and/or presentation of endogenous and exogenous MMTV ORF by lymphocyte subsets and emphasize the low threshold required for induction of peripheral T cell deletion by these gene products.

scholarly journals A Novel Block to Mouse Mammary Tumor Virus Infection of Lymphocytes in B10.BR Mice

2007 ◽  
Vol 82 (3) ◽  
pp. 1314-1322 ◽  
Author(s):  
Chioma M. Okeoma ◽  
Ming Shen ◽  
Susan R. Ross
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mammary Tumor ◽  
Mouse Mammary Tumor Virus ◽  
Cell Activation ◽  
Mouse Strains ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Tumor Virus ◽  
Mhc Locus

ABSTRACT Classic studies on C57BL-derived mouse strains showed that they were resistant to mouse mammary tumor virus (MMTV) infection. Although one form of resistance mapped to the major histocompatibility complex (MHC) locus, at least one other, unknown gene was implicated in this resistance. We show here that B10.BR mice, which are derived from C57BL mice but have the same MHC locus (H-2 k ) as susceptible C3H/HeN mice, are resistant to MMTV, and show a lack of virus spread in their lymphoid compartments but not their mammary epithelial cells. Although in vivo virus superantigen (Sag)-mediated activation of T cells was similar in C3H/HeN and B10.BR mice, T cell-dependent B-cell and dendritic cell activation was diminished in the latter. Ex vivo, B10.BR T cells showed a diminished capacity to proliferate in response to the MMTV Sag. The genetic segregation of the resistance phenotype indicated that it maps to a single allele. These data highlight the role of Sag-dependent T-cell responses in MMTV infection and point to a novel mechanism for the resistance of mice to retroviral infection that could lead to a better understanding of the interplay between hosts and pathogens.

scholarly journals The mouse mammary tumor virus envelope gene product is required for superantigen presentation to T cells.

1994 ◽  
Vol 179 (2) ◽  
pp. 439-446 ◽  
Author(s):  
T V Golovkina ◽  
A Chervonsky ◽  
J A Prescott ◽  
C A Janeway ◽  
S R Ross
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Product ◽  
Mammary Tumor ◽  
Mouse Mammary Tumor Virus ◽  
Envelope Gene ◽  
Mammary Tumor Virus ◽  
Cell Surface Glycoprotein ◽  
Mouse Mammary Tumor ◽  
Tumor Virus

Transgenic mice expressing either the mouse mammary tumor virus (MMTV) superantigen gene (sag) alone or in combination with the viral envelope genes (env) (LEL), or all of the viral genes (gag, pol, env, and sag) (HYB PRO), deleted V beta 14+ T cells from their immune repertoire. However, only LEL or HYB PRO transgenic antigen-presenting cells were capable of stimulating a proliferative response from nontransgenic primary T cells or interleukin 2 production from a V beta 15-bearing T cell hybridoma. These T cell responses could be inhibited by a monospecific antibody directed against the MMTV gp52 cell surface glycoprotein. These results indicate that the MMTV gp52 gene product participates in the presentation of superantigen to T cells, resulting in their stimulation, a requisite step in the MMTV infection pathway. Thus, gp52 could play a role in the transfer of virus between different subsets of lymphocytes.

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

1993 ◽  
Vol 177 (2) ◽  
pp. 359-366 ◽  
Author(s):  
W Held ◽  
A N Shakhov ◽  
S Izui ◽  
G A Waanders ◽  
L Scarpellino ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Mammary Tumor ◽  
Mouse Mammary Tumor Virus ◽  
Large Fraction ◽  
Cell Receptor ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Tumor Virus

Superantigens are defined by their ability to stimulate a large fraction of T cells via interaction with the T cell receptor (TCR) V beta domain. Endogenous superantigens, classically termed minor lymphocyte-stimulating (Mls) antigens, were recently identified as products of open reading frames (ORF) in integrated proviral copies of mouse mammary tumor virus (MMTV). We have described an infectious MMTV homologue of the classical endogenous superantigen Mls-1a (Mtv-7). The ORF molecules of both the endogenous Mtv-7 and the infectious MMTV(SW) interact with T cells expressing the TCR V beta 6, 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 beta 6+ CDC4+ T cells, which interact with the viral ORF. 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.

scholarly journals Identification of Key Amino Acids of the Mouse Mammary Tumor Virus Superantigen Involved in the Specific Interaction with T-Cell Receptor Vβ Domains

2001 ◽  
Vol 75 (16) ◽  
pp. 7453-7461 ◽  
Author(s):  
Frédéric Baribaud ◽  
Susanne Wirth ◽  
Ivan Maillard ◽  
Sandrine Valsesia ◽  
Hans Acha-Orbea ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cell ◽  
T Cell Receptor ◽  
Mammary Tumor ◽  
Mouse Mammary Tumor Virus ◽  
Specific Interaction ◽  
Cell Receptor ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Tumor Virus

ABSTRACT Mouse mammary tumor virus (MMTV) is a retrovirus encoding a superantigen that is recognized in association with major histocompatibility complex class II by the variable region of the beta chain (Vβ) of the T-cell receptor. The C-terminal 30 to 40 amino acids of the superantigen of different MMTVs display high sequence variability that correlates with the recognition of particular T-cell receptor Vβ chains. Interestingly, MMTV(SIM) andmtv-8 superantigens are highly homologous but have nonoverlapping T-cell receptor Vβ specificities. To determine the importance of these few differences for specific Vβ interaction, we studied superantigen responses in mice to chimeric and mutant MMTV(SIM) and mtv-8 superantigens expressed by recombinant vaccinia viruses. We show that only a few changes (two to six residues) within the C terminus are necessary to modify superantigen recognition by specific Vβs. Thus, the introduction of the MMTV(SIM) residues 314-315 into themtv-8 superantigen greatly decreased its Vβ12 reactivity without gain of MMTV(SIM)-specific function. The introduction of MMTV(SIM)-specific residues 289 to 295, however, induced a recognition pattern that was a mixture of MMTV(SIM)- and mtv-8-specific Vβ reactivities: both weak MMTV(SIM)-specific Vβ4 and fullmtv-8-specific Vβ11 recognition were observed while Vβ12 interaction was lost. The combination of the two MMTV(SIM)-specific regions in the mtv-8superantigen established normal MMTV(SIM)-specific Vβ4 reactivity and completely abolished mtv-8-specific Vβ5, -11, and -12 interactions. These new functional superantigens with mixed Vβ recognition patterns allowed us to precisely delineate sites relevant for molecular interactions between the SIM or mtv-8 superantigen and the T-cell receptor Vβ domain within the 30 C-terminal residues of the viral superantigen.

scholarly journals Identification of Notch1 as a Frequent Target for Provirus Insertional Mutagenesis in T-Cell Lymphomas Induced by Leukemogenic Mutants of Mouse Mammary Tumor Virus

2000 ◽  
Vol 74 (20) ◽  
pp. 9786-9791 ◽  
Author(s):  
Shin-ichi Yanagawa ◽  
Jong-Seo Lee ◽  
Kazuhiro Kakimi ◽  
Yukihiro Matsuda ◽  
Tasuku Honjo ◽  
...  
Keyword(s):  
T Cell ◽  
Mammary Tumor ◽  
Mouse Mammary Tumor Virus ◽  
Insertional Mutagenesis ◽  
Wild Type Mouse ◽  
Long Terminal Repeats ◽  
Mammary Tumor Virus ◽  
T Cell Lymphomas ◽  
Mouse Mammary Tumor ◽  
Tumor Virus

ABSTRACT In contrast to wild-type mouse mammary tumor virus (MMTV), the MMTV mutants with specific deletions in the U3 region of their long terminal repeats cause T-cell lymphomas. In 30% of T-cell lymphomas arising in BALB/c mice infected with MLA-MMTV, a leukemogenic MMTV mutant, we have found that MMTV proviruses were integrated into a short region of theNotch1 genome, so that truncated Notch1transcripts encoding the transmembrane and the cytoplasmic domains of Notch1 protein could be expressed. Thus, Notch1 is a major target of provirus insertional mutagenesis in these T-cell lymphomas.

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