INTOXICATION OF HIGH-AFFINITY IL-2 RECEPTOR POSITIVE THYMOCYTES BLOCKS EARLY STAGES OF T-CELL MATURATION

Early murine fetal thymocytes express functional, high affinity IL-2 receptors as determined by: (i) the presence of IL-2R beta-chain (p75) mRNA; (ii) IL-2 (10 U/ml) induced cell proliferation/cellular maturation in lobe submersion cultures (LSC). Under the influence of IL-2, early thymocytes differentiate in vitro into more mature, early single positive CD4-CD8+ followed in vivo by double Positive CD4+CD8+ and single positive CD4+CD8-T and CD4-CD8+ thymocytes. Specific intoxication of high affinity IL-2R Positive thymocytes by recombinant interleukin-2-diphtheria toxin-related fusion protein (DAB486-IL-2) results in transient, dose dependent blockade of in vivo and in vitro thymocyte maturation. DAB486-IL-2 induced effects upon in vivo maturation are reversible within 2 weeks after cessation of drug administration. Taken together, these results demonstrate the expression of functional, high affinity IL-2 receptors on early thymocytes. Elimination of high affinity IL-2 receptor positive thymocytes with DAB486-IL-2 results in transient blockade of T cell maturation. Since DAB486-IL-2 is now in clinical trial, it is reassuring to note that it does not permanently disrupt thymic maturation.