Interference with thymocyte differentiation by an inhibitor of S-adenosylhomocysteine hydrolase.
Adenosine deaminase (ADA) deficiency causes severe combined immune-deficiency disease in humans. It is believed that the accumulation of the ADA substrate deoxyadenosine affects T cell development through interference with deoxynucleotide metabolism and/or S-adenosylmethionine-mediated methylation processes. In this study, we used a specific inhibitor of methylation, (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (FddA), to study the effect of inhibition of methylation on intrathymic T cell development in a murine model for ADA deficiency. FddA causes inhibition of thymocyte differentiation specifically at the CD8low and CD4CD8 double-positive stages. This inhibition is not due to induction of apoptosis, rather it is a result of specific inhibition of regulation of the levels of the mRNAs coding for TCR and CD4 and CD8 co-receptor molecules that normally occurs at these stages of thymocyte differentiation. We hypothesize that the transcription of these T cell-specific molecules is regulated by a common developmental stimulus involving a S-adenosylmethionine-mediated methylation step. Identification of this step will help in understanding the role of methylation in intrathymic differentiation and will also provide a molecular explanation for the tissue and developmental stage specificity observed in severe combined-immune-deficient patients with ADA deficiency.
Benveniste
P
P
Division of Immunology and Cancer Research, Hospital for Sick Children, Toronto, Ontario, Canada.
Zhu
W
W
Cohen
A
A
D000243:Adenosine Deaminase / Q000172:deficiency; D043383:Adenosylhomocysteinase; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005434:Flow Cytometry; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000187:drug effects; D016511:Severe Combined Immunodeficiency / Q000209:etiology; D016176:T-Lymphocyte Subsets / Q000187:drug effects*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects*
D011948:Receptors, Antigen, T-Cell; C055502:2-fluoro-2',3'-dideoxyadenosine; D016048:Dideoxyadenosine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000243:Adenosine Deaminase