The T-cell receptor (TCR) repertoire is selected in the thymus after rearrangement of genes encoding TCR alpha and beta chains. Selection is based on the recognition by newly emergent T cells of self-ligands associated with molecules of the major histocompatibility complex: some combinations result in positive selection, others in negative selection. Negative selection, or clonal deletion, is an important mechanism for eliminating autoreactive T cells. A group of self-ligands involved in clonal deletion was identified because they, like exogenous superantigens, were recognized by almost all T cells expressing particular TCR V beta genes. V beta 17a T cells are deleted by a tissue-specific ligand; V beta 6, V beta 7, V beta 8.1 and V beta 9 T cells are deleted by the minor lymphocyte-stimulating (Mls) determinant Mls-1a; V beta 3 T cells by Mls-2a and Mls-3a; V beta 11 T cells by ligands encoded by independently segregating genes; and V beta 5 T cells by ligands encoded by two genes. Chromosome mapping using recombinant inbred strains of mice and classic backcrosses show that Mls-1a in DBA/2 mice is encoded on chromosome 1, that one of the two ligand genes for deletion of V beta 5 T cells maps to chromosome 12 and that a ligand gene for V beta 11 deletion is linked to the CD8 locus on chromosome 6. Here we present evidence from three sets of backcross mice for concordance between V beta 11 deletion ligand genes on chromosomes 6, 12 and 14 and endogenous mouse mammary tumour virus integrant (Mtv) genomes.(ABSTRACT TRUNCATED AT 250 WORDS)

In mice, V beta-specific negative selection is mediated by a number of superantigens encoded by various mouse mammary tumor viruses. We have identified Mtv-3, Mtv-27, Mtv-44, Mtv-8, Mtv-9, Mtv-11, and MMTV(D2.GD), and have confirmed Mtv-1. Although specificities of superantigens correlate well with sequences of their carboxy terminal regions, Mtv-44 appears to be an exception: the product is specific for V beta 3, V beta 6, V beta 8.1, and V beta 9. It remains to be determined whether Mtv-44 produces one or two different superantigens to exhibit this specificity. V beta 5+ T-cell deletion is induced by two groups of superantigens: V beta 3-specific superantigens encoded by Mtv-1, Mtv-3, Mtv-6, Mtv-13, Mtv-27, and Mtv-44, and V beta 11-specific superantigens encoded by Mtv-8, Mtv-9, and Mtv-11. Furthermore, these V beta 3-specific superantigens are also specific for V beta 17a(cz). In contrast, V beta-specific positive selection and V alpha-specific positive and negative selection do not seem to involve non-H-2 (super)antigens, although their involvement can not be excluded. In the near future, superantigens, powerful modulators of T-cell functions, will be exploited for clinical applications.

A gene encoding the endogenous superantigen Mlsc, which deletes Tcrb-V3+ T cells in the NOD inbred mouse strain, was found to co-segregate with Mtv-3 on chromosome 11. This identifies a fourth gene encoding a deletion ligand for Tcrb-V3+ T cells and extends recently published observations in support of the hypothesis that a number of endogenous superantigens are the products of Mtv proviruses.

Two monoclonal antibodies, KT50 and KT65, specific for V alpha 8 have been established. This was determined as follows: (a) 4 T cell clones, C6, R1, G22 and I9, out of 43 T cell clones with various antigen specificities, major histocompatibility complex restrictions and V beta usages not only bound KT50 and KT65 but also expressed V alpha 8 mRNA, (b) KT50 and KT65 precipitated molecules from the clone C6 similar to the T cell receptor molecules precipitated in C6 cells by KT11 (anti-V beta 11) or KTL2 (anti-Ti) and (c) KT50 and KT65 were mitogenic and induced cytotoxicity. All strains of mice so far examined have populations of KT50+ and KT65+ T cells of 1.4%-3.6% and 0.9%-2.6%, respectively. Different H-2 haplotypes were not observed to affect the number of cells expressing KT50 or KT65. In addition KT15 (anti-CD8), without cross-linking to KT50 or KT65, augmented proliferation triggered by KT50 or KT65.

Non-H-2 genes responsible for negative selection of Tcrb-V11+ T cells were examined using backcross mice of various strains with C58, which does not delete Tcrb-V11+ T cells. Two independently segregating genes were found: one leading to partial deletion was closely linked to Ly-2/Ly-3 on chromosome 6, and the second giving virtually complete deletion has not yet been mapped. The A strain had only the former, whereas BALB/c, BALB.K, B10.BR, CBA-T6, C3H/He, and DBA/2 expressed both of these genes. Although a gene(s) of the NIH strain led only to partial deletion, the chromosomal localization of the gene(s) has not yet been determined: no informative polymorphic molecules are expressed from genes on chromosome 6 of this strain.