International Immunology, Vol. 14, No. 10, pp. 1169-1178,
October 2002
© 2002 Japanese Society for Immunology
Analysis of the mechanisms of human cytotoxic T lymphocyte response inhibition by NO
1 INSERM U487 ‘Cytokines et Immunologie des Tumeurs Humaines’, IFR 54 ‘Bases Moléculaires et Cellulaires de Stratégies Nouvelles en Cancérologie’, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France 2 INSERM U365, Institut Curie, 26 rue d’Ulm, 75248 Paris Cedex 05, France 3 Laboratoire d’immunogénétique cellulaire, Département d‘Immunologie, Institut Pasteur, 25 rue du Docteur Roux, 75724, Paris Cedex 15, France
Correspondence to: S. Chouaib; E-mail: chouaib{at}igr.fr
Transmitting editor: G Trinchieri
NO is a potent cellular mediator which has been shown to modulate several immune mechanisms. Using human T lymphocytes as responder cells in a primary mixed lymphocyte reaction, we demonstrated that, at the initiation of the culture, exogenously provided NO via sodium nitroprusside, in non-toxic concentrations, inhibited both allogeneic proliferative and primary cytotoxic responses in a dose-dependent manner. In contrast, it had no effect on the cytotoxic activity of established human TCR 
ß and TCR 
cytotoxic T lymphocyte (CTL) clones. The NO inhibitory effect on primary cytotoxic T cell response correlates with inhibition of T cell blastogenesis. Furthermore, under our stimulation conditions, NO induced an inhibition of IL-2 production, an alteration of IL-2R expression, and a down-regulation of NF-AT translocation in CD4+ and CD8+ allostimulated T cells. Furthermore, we demonstrate that the inhibition of allospecific CTL activity by the NO donor was at least in part related to an inhibition of granzyme B and Fas ligand transcription as revealed respectively by RNase protection and RT-PCR analysis. These results suggest that NO may function to fine tune human CD3+ T cell activation and subsequent CTL generation.
Keywords: CTL, cytokines, NO
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