RNA degradation precedes DNA cleavage in autoreactive CD4 T cells suppressed by calicheamicin γ1

Calicheamicin γ1 (Cal γ1) is a hydrophobic enediyne antibiotic known to cleave the DNA and lead to apoptosis in a variety of cells. Herein, we show that Cal γ1 exhibits a 1000-times stronger suppressogenic effect on antigen-specific (diabetogenic), and naïve CD4 T cells than Doxorubicin (Dox), another strong apoptotic drug. The thymic precursors and mature T cells incubated with Cal γ1 for only 30 min showed a drastic decrease or loss of cytokine production and proliferation following stimulation with the immunogenic peptide, or with CD3 and CD28 antibodies. The suppressogenicity of Cal γ1 correlated with a rapid and non-selective degradation of RNA, whereas the DNA cleavage occurred at a later time point and at higher doses. Cal γ1 may represent a potential therapeutic agent to eliminate self-reactive T cells in autoimmune diseases, providing that is delivered by antigen-specific T-cell ligands. Targeting of highly suppressogenic drugs such as Cal γ1 to autoreactive T cells may reduce considerable the therapeutic dose and the drug-related side effects.