Inhibition of thymidine synthesis by folate analogues induces a Fas–Fas ligand-independent deletion of superantigen-reactive peripheral T cells

• Published in: International immunology Vol. 13; no. 1; pp. 85 - 93
• Main Authors: Izeradjene, Kamel, Revillard, Jean-Pierre, Genestier, Laurent
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.01.2001; Oxford Publishing Limited (England)
• Subjects: Animals; apoptosis; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Clonal Deletion - drug effects; deletion; DHFR dihydrofolate reductase; Enterotoxins - administration & dosage; Fas antigen; Fas Ligand Protein; fas Receptor - physiology; FasL Fas ligand; FasL protein; folic acid; Folic Acid Antagonists - pharmacology; Growth Inhibitors - administration & dosage; Growth Inhibitors - pharmacology; Injections, Intraperitoneal; Injections, Intravenous; interleukin 2 receptors; Ligands; Lymphocyte Activation - drug effects; Lymphocyte Depletion; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; methotrexate; Methotrexate - pharmacology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred MRL lpr; MTX methotrexate; Nucleic Acid Synthesis Inhibitors - pharmacology; PE phycoerythrin; Quinazolines - pharmacology; SEB staphylococcal enterotoxin B; Staphylococcus aureus - immunology; superantigen; Superantigens - immunology; T-Lymphocyte Subsets - enzymology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Thiophenes - pharmacology; thymidine; Thymidine - antagonists & inhibitors; Thymidine - biosynthesis; Thymidylate Synthase - antagonists & inhibitors; TNF tumor necrosis factor; tomudex; TS thymidylate synthase; TUNEL terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/13.1.85

Methotrexate (MTX), a folate antagonist with multiple enzymatic targets, is used in the treatment of malignancies as well as in autoimmune and chronic inflammatory diseases, and ZD1694 (tomudex), a water-soluble quinazoline specific inhibitor of thymidylate synthase (TS), is used in the treatment of adenocarcinomas. In this study, we investigated the effects of these folate analogues on superantigen (SAg)-reactive peripheral T cells in vivo. In BALB/c mice, staphylococcal enterotoxin B (SEB)-induced cytokine secretion, IL-2R (CD25) expression and early deletion of a fraction of SEB-reactive Vβ8+ T cells were not impaired by either MTX (7 mg/kg/day) or tomudex (5 mg/kg/day). However, both MTX and tomudex prevented Vβ8-selective T cell expansion and accelerated their peripheral elimination. Administration of thymidine (500 mg/kg/12 h) completely abrogated this effect, indicating that inhibition of TS but not that of other folate-dependent enzymes was the main mechanism involved. Furthermore, a marked increase of apoptotic cells restricted to the Vβ8+ T cell subset indicated that proliferation inhibition was associated with apoptosis. In contrast with peripheral Vβ8+ T cell deletion, MTX and tomudex did not prevent the increase of Vβ8+ thymocytes triggered by SEB. Experiments in C57BL/6-lpr/lpr mice further demonstrated that deletion of Vβ8+ T cells induced by folate analogues was independent of Fas–Fas ligand interaction. Our results provide evidence that folate analogues may selectively delete dividing peripheral T cells through TS inhibition, but do not interfere with other events triggered by SAg.