Cyclosporin A inhibits positive selection and delays negative selection in αβ TCR transgenic mice

Cyclosporin A (CsA) is an immunosuppressive drug that inhibits TCR- mediated signal transduction. This drug has two major effects on developing αβ thymocytes in normal mice: it blocks the development of most mature CD4⁺8^- and CD4^-8⁺ thymocytes and inhibits the deletion of some but not all self-specific thymocytes. The latter effect may explain how CsA treatment can paradoxically induce autoimmunity in certain situations. Here we investigated the effects of CsA on thymocyte development in transgenic mice that express on most of their T cells an αβ TCR specific for male H-Y Ag bound to H-2 D^b class I molecules, a model system in which positive and negative selection have been clearly defined. Positive selection occurs in female mice, resulting in the development of mature CD4^-CD8⁺ T cells, whereas negative selection occurs in male mice, resulting in the deletion of self-reactive CD4⁺8⁺ thymocytes. CsA blocked positive selection, as evidenced by the finding that most of the cells present in the thymuses of CsA-treated female mice were functionally immature precursors that expressed heat-stable Ag. In male mice, CsA delayed but did not prevent the deletion of most CD4⁺8⁺ thymocytes. A few transgenic thymocytes, however, were not deleted and achieved the TCR⁺, CD4^-8⁺ phenotype of positively selected cells. Therefore, for a small subset of thymocytes, CsA may convert a normally negatively selecting TCR signal to a positively selecting one.