RNA degradation precedes DNA cleavage in autoreactive CD4 T cells suppressed by calicheamicin gamma1.
Calicheamicin gamma1 (Cal gamma1) is a hydrophobic enediyne antibiotic known to cleave the DNA and lead to apoptosis in a variety of cells. Herein, we show that Cal gamma1 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 gamma1 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 gamma1 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 gamma1 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 gamma1 to autoreactive T cells may reduce considerable the therapeutic dose and the drug-related side effects.
Thomas
Sunil
S
Mount Sinai School of Medicine, Department of Microbiology, 1 Gustave L. Levy Place, New York, NY 10029, USA.
Preda-Pais
Anca
A
Casares
Sofia
S
Brumeanu
Teodor-D
TD
D000617:Aminoglycosides / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D053281:Enediynes; D051379:Mice; D008807:Mice, Inbred BALB C; D020871:RNA Stability / Q000187:drug effects*
D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; C055955:calicheamicin gamma(1)I; D004317:Doxorubicin; D004247:DNA