MOUSE MAMMARY-TUMOR VIRUS-MEDIATED T-CELL RECEPTOR-NEGATIVE SELECTION IN HLA-DRA TRANSGENIC MICE

Products of specific mouse Mtv genes expressed in association with mouse MHC class II products cause the deletion of T cells expressing particular TCR Vbeta gene segments. These endogenous deletion ligands have been termed superantigens due to their ability to negatively select entire T-cell families, as defined by Vbeta-chain usage. In most cases, deletion is preferentially effected through interaction of the Mtv ligand with H-2E products. Although human DRalpha shares only 75% identity with the Ea chain of H-2E, it has previously been shown to substitute for the mouse homologue in its capacity to induce the deletion of Vbeta11- and Vbeta17a-bearing T cells. In the present study, we have undertaken a more comprehensive analysis of the interaction of mixed DRalpha/Ebeta pairs with various endogenous Mtv integrants in various mouse backgrounds, leading to negative selection of particular Vbeta families. We show in this paper that transgenic DRalpha/Ebeta can also efficiently interact with products of Mtv-7, causing deletion of both Vbeta+ and Vbeta7+ cells. Deletion of Vbeta11 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. Sequence comparison of various HLA and H-2 molecules shown to mediate Vbeta11 deletion enabled us to make tentative predictions about residues involved in superantigen binding.