Title

The roles of recent thymic emigrants in cyclosporin A-induced autologous graft-versus-host disease

Date of Completion

January 1999

Keywords

Biology, Molecular|Health Sciences, Immunology

Degree

Ph.D.

Abstract

Cyclosporin-A (CSA)-induced autologous graft-versus-host disease (autoGVHD) is an autoimmune syndrome mediated by the export of autoeffector T cells from the thymus during CSA treatment. Prevention of autoGVHD by immunoregulatory T cells after cessation of CSA treatment is also a thymus-dependent process, although the origin of these cells is unclear. In the present study, we have tested the hypothesis that both autoeffector and immunoregulatory T cells in CSA-treated rats are recent thymic emigrants (RTEs). In addition, we determined the phenotypes of autoeffector and immunoregulatory cells in both thymus and peripheral lymph node (LN) during as well as after CSA treatment. The results showed that autoeffector T cells having a CD4+8+ (double positive, DP) phenotype transiently appear in the thymus during the first week of CSA treatment, after which they appear and persist in LN, where they display a CD48+ (single positive, SP) phenotype. Timed thymectomy experiments revealed that most of these autoeffector T cells are exported to the periphery during the first 5 days of CSA treatment, after which the thymus no longer is required to induce autoGVHD. In contrast, immunoregulatory T cells having a DP phenotype were first detected in the thymus during the second week of CSA treatment, and persisted until after cessation of CSA treatment, when they acquired a CD4+8 SP phenotype. These CD4+ SP immunoregulatory thymocytes were then exported to periphery, where they persisted for at least two weeks. Both the autoeffector and immunoregulatory T cells in peripheral LN had a Thy1+ phenotype, which is a selective marker for RTEs in the rat. Our results also demonstrated that autoeffector T cells persist in the periphery, but their function is inhibited by immunoregulatory rather than cytotoxic T cells. These results directly demonstrate that both autoeffector and immunoregulatory T cells in CSA-induced autoGVHD are RTEs; and that their formation in and release from the thymus are tightly coordinated so as to prevent the clinical expression of GVHD despite abnormalities in negative selection for self-MHC class II. Hence, CSA-induced auto GVHD appears to be a protypical model of both centrally-induced autoimmunity and non-deletional (“dominant”) tolerance. ^