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

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Lipid Rafts Activation of a Neutral Sphingomyelinase in T Cells by + and Proliferation of Human CD4 Cholera Toxin B-Subunit Prev Cholera Toxin B-Subunit Prevents Activation and Proliferation of Human CD4 + T Cells by Activation of a Neutral Sphingomyelinase in Lipid Rafts This information is current as of October 1, 2021. Alexandre K. Rouquette-Jazdanian, Arnaud Foussat, Laurence Lamy, Claudette Pelassy, Patricia Lagadec, Jean-Philippe Breittmayer and Claude Aussel J Immunol 2005; 175:5637-5648; ; doi: 10.4049/jimmunol.175.9.5637 Downloaded from http://www.jimmunol.org/content/175/9/5637 References This article cites 55 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/175/9/5637.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology 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 Aussel2* 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 Downloaded from 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. The Journal of Immunology, 2005, 175: 5637–5648. holera toxin B-subunit (CTB)3, produced by the bacte- release of IL-10, IL-6, and TNF-␣ by human monocytes (5). CTB rium Vibrio cholerae, exerts profound immunomodula- modulates Ag processing and presentation by macrophages (6–8). http://www.jimmunol.org/ C tory effects on blood cell populations in vitro. CTB trig- CTB inhibits CD3- and PMA/ionomycin-induced murine T cell gers the polyclonal activation of B cells. This activation occurs in proliferation (9, 10). Such proliferation is inhibited even if CTB is the absence of significant proliferation and involves the up-regu- added hours after the start of culture (10). CTB also inhibits the lation of a number of important molecules, namely MHC class II proliferation of 2.10 cells (a human IL-2-dependent, CD4Ϫ T cell (Ia), B7, CD40, ICAM-1, and IL-2R␣ (CD25) (1, 2). CTB induces clone) in response to IL-2 produced endogenously on stimulation selective apoptosis of T CD8ϩ cells. This apoptosis is preceded by with anti-TCR or provided exogenously (11). ETB induces nuclear enhanced expression of CD25 and is independent of Fas (CD95) or translocation of NF-␬B in Jurkat cells (12). To conclude, CTB TNF-␣. It involves a NF-␬B-dependent and caspase-3-dependent displays pleiotropic effects on human PBMCs (hPBMCs), it inhib- by guest on October 1, 2021 pathway (3). A similar effect is exerted by CTB in vivo where oral its CD4ϩ T cell activation and proliferation, but the exact mech- administration of CTB leads to a demonstrable depletion of CD8ϩ anism remained unclear. T cells from both the Peyer’s patch and intraepithelial lymphocyte In this study, our results explain the inhibitory effect of rCTB compartments (4). Heat-labile enterotoxin B-subunit (ETB) from both on the activation and on the proliferation of human CD4ϩ T Escherichia coli, which is a close homologue of CTB, induces the lymphocytes. rCTB specifically binds to the monosialoganglioside GM1, a raft marker, and strongly alters the lipid composition of rafts of CD4ϩ T lymphocytes. First, rCTB inhibits sphingomyelin *Institut National de la Sante´et de la Recherche Me´dicale (INSERM) Unit 576, IFR (SM) synthesis, secondly it enhances phosphatidylcholine (Ptd- 50, Hoˆpital de l’Archet I, Nice Cedex 3, France; and †INSERM Unit 526, Activation Cho) synthesis, and thirdly it activates a raft-resident neutral sphin- des Cellules He´matopoı¨e´tiques, Physiologie de la Survie et de la Mort Cellulaires et Infections Virales, IFR 50 Ge´ne´tique et Signalisation Mole´culaires, Faculte´deMe´- gomyelinase (SMase) resembling to NSM1, thus generating a tran- decine Pasteur, Nice Cedex 2, France sient ceramide production. We demonstrated that these ceramides Received for publication July 29, 2004. Accepted for publication August 8, 2005. inhibit protein kinase C␣ (PKC␣) phosphorylation and its trans- The costs of publication of this article were defrayed in part by the payment of page location into the modified lipid rafts. We also demonstrated that charges. This article must therefore be hereby marked advertisement in accordance rCTB as ETB activates the NF-␬B transcription factor. Further- with 18 U.S.C. Section 1734 solely to indicate this fact. more, we also show that rCTB induces NF-␬B activation via the 1 This work was supported by Institut National de la Sante´et de la Recherche Me´di- production of ceramides. Combined all together, raft modification cale. A.K.R.-J. is a recipient of a doctoral fellowship from the Ministe`re de l’Enseignement Supe´rieur et de la Recherche and from the Association pour la Re- in terms of lipids, ceramide production, PKC␣ inhibition, and cherche sur le Cancer. NF-␬B activation lead to CD4ϩ T cell inhibition. 2 Address correspondence and reprint requests to Dr. Claude Aussel, Institut National de la Sante´et de la Recherche Me´dicale Unit 576, IFR 50, Hoˆpital de l’Archet I, 151 Materials and Methods Route de Saint Antoine de Ginestie`re, B.P. 79, 06202 Nice Cedex 3, France. E-mail address: [email protected] Cells 3 Abbreviations used in this paper: CTB, cholera toxin B-subunit; ETB, enterotoxin Citrate anticoagulated venous blood samples of healthy adult volunteers B-subunit; hPBMC, human PBMC; SM, sphingomyelin; PtdCho, phosphatidylcho- and buffy coats collected from normal donors by the Etablissement Fran- line; SMase, sphingomyelinase; PKC␣, protein kinase C␣; 7-AAD, 7-aminoactino- ␤ ␤ c¸ais du Sang were obtained according to institutional guidelines. hPBMCs mycin D; m- -CD, methyl- -cyclodextrin; NAC, N-acetyl-L-cysteine; GSH, gluta- were isolated from either blood samples or buffy coats by centrifugation on thione; PDMP, 1-phenyl-2-(decanoylamino)-3-morpholino-1-propanol; FB1, fumonisin B1; PNS, postnuclear supernatant; PVDF, polyvinylidene difluoride; HSB, a Ficoll-Hypaque density-gradient (1.077 g/ml). Interface PBMCs were HEPES saline buffer; DAG, diacylglycerol; C-1-P, ceramide-1-phosphate; pCTB, pu- pelleted, washed, and cultured in RPMI 1640 supplemented with 10% (v/v) rified CTB; DRM, detergent-resistant membrane; FA, fatty acid; PtdEtn, phosphati- heat-inactivated FCS, 50 U/ml penicillin G sodium, 50 ␮g/ml streptomycin dylethanolamine; ASM, acidic SMase; SMS, SM synthase. sulfate, 2 mM L-glutamine, 1 mM sodium pyruvate, 20 mM HEPES, and Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 5638 rCTB-INDUCED SMase ACTIVATION CAUSES CD4ϩ T CELL INHIBITION 1ϫ minimal essential medium nonessential amino acid solution (Invitrogen side angle light scatter. CD25 and CD69 surface expression on CD4ϩ T Life Technologies). The human leukemic T cell line Jurkat was obtained lymphocytes was determined flow cytometry after gating lymphocytes on from American Type Culture Collection. Cells were cloned by limiting the basis of membrane expression of CD4. CD25 and CD69 up-regulation dilution. Clone D was selected on the basis of its IL-2 production when was also examined on Jurkat cells pretreated or not with the indicated drugs activated with PHA and the phorbolester 12-O-tetradecanoylphorbol-13- (as detailed in the figure legends) then stimulated or not with PMA (10 acetate. Jurkat clone D were grown in the same medium as PBMCs. Cells ng/ml) plus ionomycin (100 nM) for 20 h. The mean fluorescence intensity were maintained at densities between 8 ϫ 105 and 1 ϫ 106/ml in a hu- of 5000 cells was determined by flow cytometry (FACScan; BD midified incubator under 5% CO2 (Heraeus). Biosciences). Abs, reagents, and radioactive products Viability measurement of treated cells rCTB was a kind gift of Dr. F. Anjue`re and Prof. C. Czerkinsky (U721, hPBMCs, treated or not with rCTB (10 ␮g/ml) for 72 h, were stained with Nice, France). rCTB was produced in a mutant strain of Vibrio cholerae 01 a FITC-CD4 mAb. Then cells were incubated with both annexin-PE and deleted of its CT genes and transformed with a multicopy plasmid encod- 7-AAD according to the manufacturer’s specifications. 7-AAD can be ex- ing CTB. The rCTB used was purified from the culture medium by a cited by the 488-nm argon laser line and emits in the far red range of the combination of salt precipitation and chromatographic methods, as previ- spectrum; consequently, its spectral emission can be separated from the ously described (13), and has been already used in several studies (14–16).
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