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Mouse mammary tumor virus-mediated T-cell receptor negative selection in HLA-DRA transgenic mice
D M Altmann1, K Takács, J Trowsdale
1Transplantation Biology Section, Clinical Research Centre, Harrow, London, England.
Abstract:
Products of specific mouse Mtv genes expressed in association with mouse MHC class II products cause the deletion of T cells expressing particular TCR V beta gene segments. These endogenous deletion ligands have been termed superantigens due to their ability to negatively select entire T-cell families, as defined by V beta-chain usage. In most cases, deletion is preferentially effected through interaction of the Mtv ligand with H-2E products. Although human DR alpha shares only 75% identity with the E alpha chain of H-2E, it has previously been shown to substitute for the mouse homologue in its capacity to induce the deletion of V beta 11- and V beta 17a-bearing T cells. In the present study, we have undertaken a more comprehensive analysis of the interaction of mixed DR alpha/E beta pairs with various endogenous Mtv integrants in various mouse backgrounds, leading to negative selection of particular V beta families. We show in this paper that transgenic DR alpha/E beta can also efficiently interact with products of Mtv-7, causing deletion of both V beta 6+ and V beta 7+ cells. Deletion of V beta 11+ T cells in DRA transgenic mice carrying Mtv-8 and -9, however, was less efficient than in control H-2Ea transgenic mice. These data and those from other MHC transgenic mouse studies show that while the class II alpha chain can influence the interaction with superantigen, it is the identity of the beta chain that seems to be critical.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Mouse superantigens, interacting with MHC class II molecules, delete specific T cells. Human DR alpha chains can substitute for mouse H-2E, but the beta chain
Area of Science:
- Immunology
- T-cell biology
- MHC class II interactions
Background:
- Mouse mammary tumor virus (Mtv) gene products act as superantigens.
- Superantigens mediate T-cell deletion by binding to MHC class II molecules.
- Previous studies showed human DR alpha can substitute for mouse E alpha in T-cell deletion.
Purpose of the Study:
- To comprehensively analyze the interaction of human DR alpha/mouse E beta pairs with Mtv integrants.
- To investigate the role of MHC class II alpha and beta chains in superantigen-induced T-cell deletion.
- To determine the critical chain for superantigen binding and T-cell selection.
Main Methods:
- Generation of transgenic mice expressing human DR alpha/mouse E beta.
- Analysis of T-cell receptor V beta usage in transgenic mice.
- Assessment of negative selection of T cells in response to Mtv superantigens.
Main Results:
- Transgenic DR alpha/E beta efficiently interacted with Mtv-7, deleting V beta 6+ and V beta 7+ T cells.
- Deletion of V beta 11+ T cells by Mtv-8 and -9 was less efficient with DR alpha compared to H-2Ea.
- The beta chain identity appears critical for superantigen interaction and T-cell deletion.
Conclusions:
- The beta chain of MHC class II molecules plays a critical role in superantigen specificity.
- While the alpha chain influences superantigen interaction, the beta chain dictates the selection outcome.
- These findings advance understanding of T-cell development and immune tolerance.