DEPLETION OF THE MATURE CD4(-) THYMOCYTE SUBSET BY FK506 ANALOGS CORRELATES WITH THEIR IMMUNOSUPPRESSIVE AND CALCINEURIN INHIBITORY ACTIVITIES()8()

FK506 blocks T cell activation by preventing the transcription of lymp hokine genes through binding to the intracellular protein FKBP12 and f ormation of a complex that inhibits the phosphatase activity of calcin eurin, Beside exerting potent suppressive activity on cellular and hum oral immune responses, in vivo treatment with FK506 in rodent models i nduces thymic alterations characterized by a selective reduction of ma ture CD4(+)8(-) cells, The potential relationship between such thymic alterations and the immunosuppressive and calcineurin inhibitory activ ities of FK506 has not been defined, Here, we took advantage of the av ailability of FK506 analogs with different immunosuppressive potencies to address this question, Intravenous daily administration of FK506 i n Sprague-Dawley rats for 4 days was found to be sufficient to cause a depletion of CD4(+)8(-) thymocytes, with an ED50=0.06 mg/kg/day. Unde r the same conditions, L-683,590 which is 2-3-fold less potent than FK 506 in inhibiting T cell activation and calcineurin function gave an E D50=0.17 mg/kg/day. In contrast, the nonimmunosuppressive, calcineurin noninhibitory antagonist L-685,818 failed to deplete the CD4(+)8(-) t hymocyte subset but could reverse the reducing effect of FK506 on this subset, Another analog, L-688,617, which does not completely inhibit T cell activation in vitro, also behaved as a partial agonist of CD4()8(-) cell depletion, Therefore, the ability of FK506 analogs to deple te the CD4(+)8(-) thymocyte subset correlates with their immunosuppres sive and calcineurin inhibitory potencies. This suggests that calcineu rin is involved in the intrathymic maturation processes of CD4(+)8(-) T cells. Moreover, the short-term treatment protocol described here pr ovides a rapid and quantitative assay to determine the immunosuppressi ve potency of FK506-like compounds in vivo.