KINETICS OF THYMOCYTE SUBSET DEVELOPMENT AND SELECTION REVEALED BY CYCLOSPORINE-A TREATMENT

Cyclosporin A (CsA) inhibits the development of mature thymocytes from their CD4(+)CD8(+) precursors, but may allow autoreactive cells to ma ture. Using 3-color now cytometry, we have followed the progressive de velopment of thymocytes, including potentially autoreactive cells, dur ing CsA treatment. Numbers of CD4(+)CD8(+)CD3(high) thymocytes dropped immediately, suggesting that the generation of these mature thymocyte precursors, normally dependent upon positive selection, was inhibited by CsA. Numbers of CD4(+)CD8(-) thymocytes also declined rapidly, but CD4(-)CD8(+) thymocytes were unaffected 1for 2 days, suggesting that the mature single-positive subsets are not symmetrically derived from a common GsA-sensitive precursor. An exceptional subset of CD8 SP thym ocytes, expressing CD45RA, did not respond to CsA for about 10 days, i ndicating that they are distantly derived from a CsA-sensitive precurs or. Apoptosis of TCR-V beta 3(+) thymocytes caused by Mtv-6, quantifie d according to the down-regulation of CD4 and CD8 on immature thymocyt es, was partially inhibited by CsA, to maximal effect within 24 hours. This did not, however, facilitate their development into mature thymo cytes.