International Immunology, Vol. 13, No. 1, 85-93,
January 2001
© 2001 Japanese Society for Immunology
Inhibition of thymidine synthesis by folate analogues induces a Fas–Fas ligand-independent deletion of superantigen-reactive peripheral T cells
Laboratory of Immunopharmacology, Institut National de la Santé et de la Recherche Médicale U503, Claude Bernard University, Hopital E. Herriot, 5 Place d'Arsonval, 69437 Lyon Cedex 03, France
Correspondence to: L. Genestier
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 Vß8+ T cells were not impaired by either MTX (7 mg/kg/day) or tomudex (5 mg/kg/day). However, both MTX and tomudex prevented Vß8-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 Vß8+ T cell subset indicated that proliferation inhibition was associated with apoptosis. In contrast with peripheral Vß8+ T cell deletion, MTX and tomudex did not prevent the increase of Vß8+ thymocytes triggered by SEB. Experiments in C57BL/6-lpr/lpr mice further demonstrated that deletion of Vß8+ 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.
Keywords: apoptosis, deletion, methotrexate, superantigen, tomudex
Transmitting editor: A. Fischer
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