Autocrine Nitric Oxide Modulates CD95-induced Apoptosis in γδ T Lymphocytes*
- Clara Sciorati‡,
- Patrizia Rovere§,
- Marina Ferrarini§,
- Silvia Heltai§,
- Angelo A. Manfredi§ and
- Emilio Clementi‡¶‖
- From the ‡Receptor Biochemistry Unit, DIBIT and§Second Department of Medicine, Laboratory of Cancer Immunology, Scientific Institute Ospedale San Raffaele and the¶Department of Pharmacology, School of Pharmacy, CNR-IBAF, University of Reggio Calabria, 88021 Catanzaro and Consiglio Nazionale delle Ricerche Cellular and Molecular Pharmacology Centre, Via Olgettina 58, 20132 Milano, Italy
Abstract
γδ T lymphocytes play an important early role in the defense against pathogens. Their function is terminated by acquisition of susceptibility to CD95-triggered apoptosis. Here we show that the regulation of this process depends on the activity of the endothelial NO synthase expressed by γδ T lymphocytes, which is modulated in an activation-dependent way. The effects of nitric oxide thus generated, mediated via cGMP generation, are exerted at at least two sites along the CD95 signaling cascade: one at, or upstream, and the other downstream of ceramide generation. At either site, nitric oxide/cGMP action is sufficient for protection from apoptosis. The effect of NO is selective for apoptosis induced by CD95 cross-linking, since it does not affect apoptotic program triggered by other stimuli. The evidence here reported demonstrates a new physiological role for nitric oxide, acting as a survival factor for T lymphocytes.
Footnotes
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↵* This work was supported by a grant from Istituto Superiore di Sanità (progetto Tubercolosi) (to A. M.), a grant from the Italian Association of Cancer Research (to J. M.), and the “Mario e Valeria Rindi” fellowship of the Fondazione Italiana per la Ricerca sul Cancro (to P. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‖ To whom correspondence should be addressed: Dip. Farmacologia, DIBIT, Scientific Institute San Raffaele, Via Olgettina 58, 20132 Milano, Italy. Tel.: 39-2-26432770; Fax: 39-2-26434813; E-mail:clemene{at}dibit.hsr.it.
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↵1 The abbreviations used are: TcR, T cell receptor; mAb, monoclonal antibody; ecNOS, endothelial nitric oxide synthase; SNAP, S-nitrosoacetylpenicillamine; acYVAD-CMK, ac-Tyr-Val-Ala-Asp-chloromethyl ketone; ODQ, H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one;l-NAME,N ω-nitro-l-arginine methyl ester; l-NIO,l-N-(iminoethyl)-ornithine; PBS, phosphate-buffered saline; PI, propidium iodide; [Ca2+]i, cytosolic Ca2+concentration; NOS, nitric oxide synthase; 8-Br, 8-bromo; Ab, antibody; FITC, fluorescein isothiocyanate.
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- Received June 20, 1997.
