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Cholera Toxin B-Subunit Prevents Activation and Proliferation of Human CD4⁺ T Cells by Activation of a Neutral Sphingomyelinase in Lipid Rafts¹

Alexandre K. Rouquette-Jazdanian^*, Arnaud Foussat^*, Laurence Lamy^*, Claudette Pelassy^*, Patricia Lagadec, Jean-Philippe Breittmayer^* and Claude Aussel^2,*

^* Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 576, IFR 50, Hôpital de l’Archet I, Nice Cedex 3, France; and INSERM Unit 526, Activation des Cellules Hématopoïétiques, Physiologie de la Survie et de la Mort Cellulaires et Infections Virales, IFR 50 Génétique et Signalisation Moléculaires, Faculté de Médecine Pasteur, Nice Cedex 2, France

The inhibition of human CD4⁺ T lymphocyte activation and proliferation by cholera toxin B-subunit (CTB) is a well-established phenomenon; nevertheless, the exact mechanism remained unclear. In the present study, we propose an explanation for the rCTB-induced inhibition of CD4⁺ T lymphocytes. rCTB specifically binds to GM1, a raft marker, and strongly modifies the lipid composition of rafts. First, rCTB inhibits sphingomyelin synthesis; second, it enhances phosphatidylcholine synthesis; and third, it activates a raft-resident neutral sphingomyelinase resembling to neutral sphingomyelinase type 1, thus generating a transient ceramide production. We demonstrated that these ceramides inhibit protein kinase C phosphorylation and its translocation into the modified lipid rafts. Furthermore, we show that rCTB-induced ceramide production activate NF-B. Combined all together: raft modification in terms of lipids, ceramide production, protein kinase C inhibition, and NF-B activation lead to CD4⁺ T cell inhibition.

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