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Molecular characterization of Mls-1
1Department of Pathology, Tufts University School of Medicine, Boston, MA 02111.
Abstract:
Recently a series of endogenous and exogenous superantigens have been described which have one common feature, namely, they lead to in vivo deletion and in vitro stimulation of T cells expressing particular T cell receptor V beta genes. The Mls antigens represent the prototypes of these molecules. We have mapped Mls-1 to the endogenous mammary tumor virus (MMTV) Mtv-7, while other SAG have also been associated with various MMTV. The open reading frame gene of the MMTV encodes the SAG. Thus, the new terminology MMTV sag has been proposed for this gene. Transfection experiments suggest that the expression of MMTV sag is tightly controlled, probably by a negative acting factor encoded within the open reading frame. Furthermore, a pronounced IL-4 effect is seen in the functional detection of the transfected Mtv-7 sag. Since this lymphokine does not influence the mRNA level of the endogenous or transfected MMTV genes, it is likely that it exerts its effect by increasing transcription of MHC class II genes, whose products are required for functional detection of Mls. We have identified one mouse strain, MA/MyJ, which has an Mls-1 phenotype but does not contain Mtv-7. The SAG activity of this strain was mapped to a new mammary tumor provirus, Mtv-43, not seen in other inbred strains. Sequence analyses revealed that the predicted amino acid sequences of the Mtv-7 and the Mtv-43 sag genes are very similar. This is particularly striking in the C-terminus, where all other MMTV sag sequences differ 100%. Thus, this region of the molecule seems to control the V beta specificity of SAG molecules. It is likely that the SAG expression provides an advantage for the infectious MMTV, probably by facilitating its transmission by T cells from the site of primary residence in the gut to its final destination, the mammary glands.
Insights
Mammary tumor viruses (MMTV) encode superantigens (SAG) that control T cell receptor V beta gene expression. These MMTV SAGs, like Mtv-7 and Mtv-43, are crucial for MMTV transmission and may influence T cell responses.
Area of Science:
- Immunology
- Virology
- Genetics
Background:
- Superantigens (SAGs) are known to delete and stimulate T cells expressing specific T cell receptor V beta genes.
- Mammary tumor viruses (MMTV) are associated with various SAGs, with Mls antigens serving as prototypes.
- The MMTV open reading frame gene encodes SAGs, leading to the proposed terminology MMTV sag.
Purpose of the Study:
- To investigate the genetic basis and functional characteristics of MMTV-encoded superantigens.
- To identify novel MMTV proviruses associated with SAG activity.
- To elucidate the role of MMTV SAGs in T cell receptor specificity and viral transmission.
Main Methods:
- Mapping of Mls-1 to MMTV Mtv-7 and identification of Mtv-43 in a novel mouse strain.
- Transfection experiments to study MMTV sag expression control.
- IL-4 treatment to assess functional detection of MMTV sag and its effect on MHC class II gene transcription.
- Sequence analysis of Mtv-7 and Mtv-43 sag genes.
Main Results:
- MMTV sag expression is tightly regulated, potentially by a negative factor within the open reading frame.
- IL-4 enhances functional detection of Mtv-7 sag by increasing MHC class II gene transcription, not mRNA levels.
- A novel MMTV provirus, Mtv-43, was identified with Mls-1 phenotype in a mouse strain lacking Mtv-7.
- High sequence similarity between Mtv-7 and Mtv-43 sag genes, particularly at the C-terminus, suggests a role in V beta specificity.
Conclusions:
- MMTV SAGs play a critical role in shaping T cell responses by targeting specific T cell receptor V beta genes.
- The C-terminal region of MMTV SAGs is likely responsible for determining their V beta specificity.
- MMTV SAG expression may confer a transmission advantage to the infectious MMTV by facilitating T cell-mediated spread from the gut to mammary glands.