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Differences in the avidity of TCR interactions with a superantigenic ligand affect negative selection but do not
A V Chervonsky1, T V Golovkina, S R Ross
1Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Abstract:
The products of the sag genes of the exogenous mouse mammary tumor virus (MMTV) genome and of endogenous Mtv integrants have been demonstrated to affect the T cell repertoire in mice by causing the deletion of T cells expressing receptors encoded by particular V beta gene segments. Since these deletions affect large populations of T cells with receptors of heterogeneous specificity, they serve as an important model for the study of T cell development in normal mice. Using several C3H/HeN-based strains that express different MMTV(C3H) transgenes, we demonstrate here that the stage of development at which T cell deletion occurs is determined by the level of ligand expression. Although at low levels of ligand expression in the thymus some signs of activation were observed in immature thymocytes, we were unable to detect a level of Sag expression that led to net positive selection. Moreover, we detected a level of Sag-transgene expression that did not cause negative selection in the thymus; no signs of positive selection were observed either. Inclusion of the env gene in the construct, earlier shown to markedly potentiate stimulation by Sag in mixed lymphocyte reactions, also markedly increased the ability of Sag to drive negative selection. These data are interpreted as showing that marked quantitative differences in expression of superantigens does not reveal a level at which only positive selection occurs. This, in turn, suggests that positive selection will occur on ligands distinct from those that drive clonal deletion.
Insights
Mouse mammary tumor virus (MMTV) superantigens delete specific T cells during development. The level of ligand expression, not just quantity, dictates T cell deletion timing and suggests positive selection involves different ligands.
Area of Science:
- Immunology
- T cell development
- Virology
Background:
- Mouse mammary tumor virus (MMTV) superantigens (Sag) influence T cell repertoire by deleting T cells with specific V beta gene segments.
- These deletions serve as a model for studying T cell development due to the large populations affected.
Purpose of the Study:
- To investigate how ligand expression levels of MMTV superantigens affect T cell development stages.
- To determine if a threshold exists for Sag expression that promotes positive selection without negative selection.
Main Methods:
- Utilized C3H/HeN-based mouse strains expressing different MMTV(C3H) transgenes.
- Analyzed T cell deletion and activation in immature thymocytes at varying Sag ligand expression levels.
- Examined the effect of including the env gene in constructs on Sag-mediated T cell selection.
Main Results:
- T cell deletion timing is dependent on the level of ligand expression.
- No Sag expression level was found to induce net positive selection; low levels showed some activation but no net gain.
- A level of Sag expression was identified that did not cause negative selection, but also showed no positive selection.
- Inclusion of the env gene significantly enhanced Sag's ability to induce negative selection.
Conclusions:
- Quantitative differences in superantigen expression do not reveal a level promoting only positive selection.
- Positive selection likely occurs in response to ligands distinct from those mediating clonal deletion (negative selection).