FK506 inhibits the differentiation of developing thymocytes but not negative selection of T cell receptor V beta 5+ and V beta 11+ T lymphocytes in vivo.

To examine the influence of FK506 on lymphocyte development, we employed a syngeneic bone marrow transplantation model using MHC-disparate B10 (H-2b, I-Ab) and B10.BR (H-2k, I-Ak, I-Ek) mice. B10 mice, which do not express class II I-E, do not delete any known T cell receptor (TCR)-V beta, while B10.BR mice (MHC class II I-Ek, I-Ak) delete V beta 5+ and V beta 11+ TCR. Continuous daily treatment of syngeneically reconstituted B10 mice with FK506 delayed the development of thymocytes from the CD4+CD8+ to CD4+CD8- stage, while no effect was observed at the earlier CD4-CD8- to CD4+CD8+ stage. At the same time, there was a significant reduction in TCRhigh thymocytes compared with untreated, syngeneically reconstituted controls. These results suggest that FK506 treatment interfered with thymic positive selection. We also examined whether FK506 treatment would influence negative selection. Levels of expression of V beta 5+ and V beta 11+ T cells in FK506-treated B10.BR-->B10.BR recipients were similar to those observed in unmanipulated, syngeneically reconstituted B10.BR-->B10.BR controls. This was not due to the inhibition of clonal proliferation by FK506, since 35 days after drug withdrawal complete recovery of the peripheral Thy1.2+ population was observed, while the percentages of V beta 5+ and V beta 11+Thy1.2+ T cells were maintained at values similar to controls. Surprisingly, clonal proliferation stimulated by monoclonal antibody against V beta 5 and V beta 11 TCRs was observed in CsA-treated, syngeneically reconstituted B10.BR mice but not in FK506-treated mice, suggesting that CsA may be more likely to induce autoreactivity. Differences in thymic architecture between FK506- and CsA-treated animals further suggested that the drugs may differ in their effects on T cell development in vivo.