The Journal of Immunology, Vol 155, Issue 2 536-544, Copyright © 1995 by American Association of Immunologists

ARTICLES

Interference with thymocyte differentiation by an inhibitor of S- adenosylhomocysteine hydrolase

P Benveniste, W Zhu and A Cohen
Division of Immunology and Cancer Research, Hospital for Sick Children, Toronto, Ontario, Canada.

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.

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