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.

Tumour necrosis factor (TNF), jointly referring to TNF alpha and TNF beta, is a central mediator of immune and inflammatory responses; its activities are mediated by two distinct receptors, TNFR1 (p55) and TNFR2 (p75) (reviewed in refs 1-3). The cytoplasmic domains of the TNFRs are unrelated, suggesting that they link to different intracellular signalling pathways. Although most TNF responses have been assigned to one or the other of the TNF receptors (mostly TNFR1), there is no generally accepted model for the physiological role of the two receptor types. To investigate the role of TNFR1 in beneficial and detrimental activities of TNF, we generated TNFR1-deficient mice by gene targeting. We report here that mice homozygous for a disrupted Tnfr1 allele (Tnfr1(0)) are resistant to the lethal effect of low doses of lipopolysaccharide after sensitization with D-galactosamine, but remain sensitive to high doses of lipopolysaccharide. The increased susceptibility of Tnfr1(0)/Tnfr1(0) mutant mice to infection with the facultative intracellular bacterium Listeria monocytogenes indicates an essential role of TNF in nonspecific immunity.

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The MHC class II gene Aa was disrupted by targeted mutation In embryonic stem (ES) cells derived from C57BL/6 mice to prevent expression of MHC class II molecules. Contrary to previous reports, the effect of the null-mutation on T cell development was Investigated In C57BL/6 mice, which provide a defined genetic background. The complete lack of cell surface expression of MHC class II molecules In B6-Aa°IAa° homozygous mutant mice was directly demonstrated by cytofluorometrlc analysis using antl-A b and anti-la specific mAbs. Development of CD4 + CD8" T cells In the thymus was largely absent except for a small population of thymocytes expressing high levels of CD4 together with low amounts of CDS. The majority of these cells express the TCR at high density. Although mature CD4+CD8~ T cells were undetectable In the thymus, some T cells with a CD4 + CD8~TCR hlBh phenotype were found In lymph nodes and spleen. Peripheral T cells from the mutant mice can be polyclonally activated In vitro with the mltogen concanavalln A. However, they could not be stimulated with staphylococcal enterotoxln B In autologous lymphocyte reactions, thereby demonstrating the absence of MHC class II expression in these mice. Peripheral B cells In B6-A8°/Aa° mutants were functional and responded to the T cell independent antigen levan by the production of antigenspecific IgM antibodies similar to wild-type cells. The B6-Aa°IAa° mutant mice described In this study represent an important tool to Investigate the Involvement of MHC class II molecules in lymphocyte maturation and the Immune response.