THE EFFECT OF RAPAMYCIN ON T-CELL DEVELOPMENT IN MICE

Rapamycin (RAPA) is a strong immunosuppressant with a chemical structure similar to that of FK506, although it acts by a mechanism different from both FK506 and cyclosporin A. The effect of RAPA on T cell development in mice was investigated in this study. RAPA caused significant thymic atrophy. The major histological change in the RAPA-treated thymus was thinning of the cortex. No other apparent damage in the cortex or medulla was observed. Consistent with these histological findings, in vivo thymocyte cycling was blocked by RAPA before the S phase, and the ex vivo and in vitro proliferation of the thymocytes was also strongly repressed by the drug. According to electron microscopy and DNA fragmentation assays, RAPA did not induce apoptosis. These results indicate that the repressed thymocyte proliferation is a major mechanism causing RAPA-induced thymic atrophy. Further, RAPA had no effect on thymocyte apoptosis induced by anti-CD3 or ionomycin, and the drug did not interfere with deletion of CD4(+)8(+) thymocytes or peripheral V beta 6(+) T cells induced by anti-CD3 or Mls-1(a), respectively. These data suggest that RAPA does not hamper the negative selection. There was a relative increase in the CD3(-) fraction of the de novo developing CD3 and CD8 double-positive (DP) thymocytes in the RAPA-treated mice. Moreover, there were relative increases of the CD3(-) fractions of the CD4 or CD8 single-positive (SP) cells in both the thymi and periphery. The generation of the CD3(-) SP under the influence of RAPA could be used as a useful model for further study of the function and signal transduction of these CD3-defective SP cells.