The mechanism of self-tolerance is studied in T-cell-receptor transgenic mice expressing a receptor in many of their T cells for the male (H-Y) antigen in the context of class I H-2Db MHC antigens. Autospecific T cells are deleted in male mice. The deletion affects only transgene-expressing cells with a relatively high surface-density of CD8 molecules, including nonmature CD4+ CD8+ thymocytes, and is not caused by anti-idiotype cells.

The heterogeneity of ␥-aminobutyric acid type A (GABAA) receptors contributes to the diversity of neuronal inhibition in the regulation of information processing. Although most GABA A receptors are located synaptically, the small population of ␣5GABAA receptors is largely expressed extrasynaptically. To clarify the role of the ␣5GABAA receptors in the control of behavior, a histidineto-arginine point mutation was introduced in position 105 of the murine ␣5 subunit gene, which rendered the ␣5GABAA receptors diazepam-insensitive. Apart from an incomplete muscle relaxing effect, neither the sedative, anticonvulsant, nor anxiolytic-like activity of diazepam was impaired in ␣5(H105R) mice. However, in hippocampal pyramidal cells, the point mutation resulted in a selective reduction of ␣5GABAA receptors, which altered the drugindependent behavior. In line with the role of the hippocampus in certain forms of associative learning, trace fear conditioning, but not delay conditioning or contextual conditioning, was facilitated in the mutant mice. Trace fear conditioning differs from delay conditioning in that the conditioned and unconditioned stimulus are separated by a time interval. Thus, the largely extrasynaptic ␣5GABAA receptors in hippocampal pyramidal cells are implicated as control elements of the temporal association of threat cues in trace fear conditioning.

T-cell receptors and T-cell subsets were analysed in T-cell receptor transgenic mice expressing alpha and beta T-cell receptor genes isolated from a male-specific, H-2Db-restricted CD4-8+ T-cell clone. The results indicate that the specific interaction of the T-cell receptor on immature thymocytes with thymic major histocompatibility complex antigens determines the differentiation of CD4+8+ thymocytes into either CD4+8- or CD4-8+ mature T cells.

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Thymus-derived lymphocytes (T cells) recognize antigen in the context of class I or class II molecules encoded by the major histocompatibility complex (MHC) by virtue of the heterodimeric alpha beta T-cell receptor (TCR). CD4 and CD8 molecules expressed on the surface of T cells bind to nonpolymorphic portions of class II and class I MHC molecules and assist the TCR in binding and possibly in signalling. The analysis of T-cell development in TCR transgenic mice has shown that the CD4/CD8 phenotype of T cells is determined by the interaction of the alpha beta TCR expressed on immature CD4+8+ thymocytes with polymorphic domains of thymic MHC molecules in the absence of nominal antigen. Here we provide direct evidence that positive selection of antigen-specific, class I MHC-restricted CD4-8+ T cells in the thymus requires the specific interaction of the alpha beta TCR with the restricting class I MHC molecule.

THE T-cell repertoire within an individual is biased to recognize antigen in the context of self major histocompatibility complex (MHC) antigens. This is thought to depend on a process of positive selection during development. Support for this notion has recently been obtained in experiments using transgenic mice bearing genes for T-cell receptors (TCR) of defined specificity: T cells expressing the introduced genes form the main part of the mature T-cell population only in mice that express the appropriate MHC product. We have now extended these observations using TCR transgenic mice homozygous for the severe combined immunodeficiency (SCID) mutation which are defective in the rearrangement of both TCR and immunoglobulin genes. In this case mature thymocytes develop only in transgenic mice that express the MHC product which restricts the specificity of the transgenic TCR. This shows that the interaction of the alpha beta TCR with thymic MHC antigen is essential for the development of mature T cells. Furthermore, the peripheral lymph nodes of such mice are underdeveloped, suggesting that the peripheral expansion of mature T cells may require interactions with other lymphocytes expressing a range of receptors.

In B cells the loci encoding immunoglobulin chains usually show allelic exclusion; a given B cell transcribes and translates only one productively rearranged allele of the heavy and light chain loci. This ensures that each B cell expresses only one antigen receptor. The loci encoding T-cell receptor (TCR) alpha- and beta-genes may behave similarly. We have previously reported that the expression of a transgenic TCR beta-chain prevents functional and nonfunctional V beta rearrangements in the endogenous beta-chain loci but not D beta J beta rearrangements. We have also been unable to detect the expression of the TCR gamma-chain locus in thymocytes of these mice (unpublished observations). To study the mechanisms involved in forming a mature T-cell repertoire further, we have constructed mice expressing alpha- and beta-TCR transgenes derived from a cytotoxic T-cell clone that is specific for the male antigen H-Y in the context of H-2Db MHC molecules. Here we show that in these mice rearrangement of endogenous alpha-chain loci is also suppressed, although to a lesser extent than rearrangement of beta-chain loci. In addition, in male alpha beta TCR transgenic mice we observed T-cell clones which had deleted both transgenic alpha- and beta-chain genes and expressed endogenous alpha- and beta-chain TCR genes. These cells are presumably derived from rare thymocytes that leave the male thymus because their TCR no longer recognizes self antigen. The vast majority of CD4+8+ nonmature thymocytes expressing alpha- and beta-transgenes are deleted in the male thymus.

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