Analysis of the mechanisms of human cytotoxic T lymphocyte response inhibition by NO

• Published in: International immunology 2002-10, Vol.14 (10), p.1169-1178
• Main Authors: Blesson, Séverine, Thiery, Jérôme, Gaudin, Catherine, Stancou, Rodica, Kolb, Jean‐Pierre, Moreau, Jean‐Louis, Theze, Jacques, Mami‐Chouaib, Fathia, Chouaib, Salem
• Format: Article
• Language: English
• Subjects: Adult; CTL; cytokines; DNA-Binding Proteins - metabolism; Fas Ligand Protein; Granzymes; Humans; Interferon-gamma - biosynthesis; Interleukin-2 - biosynthesis; Lymphocyte Activation; Membrane Glycoproteins - genetics; NFATC Transcription Factors; Nitric Oxide - physiology; Nitroprusside - pharmacology; Nuclear Proteins; Receptors, Interleukin-2 - analysis; Serine Endopeptidases - genetics; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Transcription Factors - metabolism; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxf081

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 αβ and TCR γδ 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‐2Rα 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.