Cyclosporin A (CsA) prevents most Immature thymocytes from progressing to a mature phenotype and blocks the deletion of T cells that express self-specific TCR In the small population of cells that achieve maturity. The latter effect may explain the paradoxical observation that this immunosuppressive drug can induce autoimmunity in irradiated rodents and humans if administered while new T cells are developing In the thymus. This study shows that the repopulation of the periphery with mature T cells Is delayed in irradiated CsA-treated mice, presumably because CsA blocks T cell development in the thymus. The peripheral repertoire of these mice contained self-reactive IL-2 producing T cells that could be detected in a sensitive limiting dilution assay. In addition, self-reactive T cell hybridomas were isolated from the IL-2 receptorB population present in CsA-treated mice. One of these hybridomas expressed a TCR chain that is normally expressed on thymocytes that are deleted via recognition of self-antigens. Despite the presence of self-reactive T cells that had escaped clonal deletion, CsA-treated mice rarely developed lethal autoimmune disease, implying that a peripheral mechanism of tolerance can prevent the onset of autoimmune disease.
Bibliographical noteFunding Information:
The authors thank Lenise Burch and Mike Hupke for operating the FACS IV, William Beschorner for performing the histological analyses, and P. Sean Taylor for excellent technical assistance This work was supported by National Institutes of Health Grant AI-28365 (M.K.J.), by a Pew Scholars Award (M.K J.), and by National Institutes of Health Training Grant AI-07313 (K.B.U.).
- Negative selection
- Peripheral tolerance
- Positive selection