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Department of Pathology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030
Cyclosporin A (CSA)-induced autologous graft-vs-host disease
(autoGVHD) is an autoimmune syndrome initiated by
autoeffector T cells presumed to be exported from the thymus during CSA
treatment. The appearance of noncytotoxic immunoregulatory T cell
activity after cessation of CSA treatment is also thymus dependent. 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). Local syngeneic graft-vs-host reaction
(synGVHR) and timed thymectomy (Tx) assays revealed that
autoeffector T cells appear initially in the thymus and are promptly
exported to lymph nodes (LN) during the first week of CSA treatment. In
contrast, immunoregulatory thymocytes are first detectable by local
synGVHR inhibition assays during the second week of CSA
treatment but are not exported to LN until 
4 days post-CSA. Both the
autoeffector and immunoregulatory T cells in LN express Thy-1, a
selective marker for RTEs in the rat. However, the autoeffector RTEs
have a CD4+8+ phenotype, whereas the
immunoregulatory RTEs have a CD4+8- phenotype.
Thus, the coordinate formation in and release from the thymus cortex
and medulla of autoeffector and immunoregulatory T cells in CSA-treated
rats directly demonstrates that centrally induced, nondeletional
tolerance can serve as a fail-safe mechanism by which clones of
autoeffector T cells that have escaped intrathymic negative selection
for self-MHC class II Ag can be suppressed
postthymically.
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