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Enhanced Dendritic Cell Survival Attenuates Lipopolysaccharide-Induced Immunosuppression and Increases Resistance to Lethal Endotoxic Shock¹

Emmanuel L. Gautier^*, Thierry Huby^*,, Flora Saint-Charles^*, Betty Ouzilleau, M. John Chapman^*,, and Philippe Lesnik^2,*,,

^* Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S551, Dyslipoproteinemia and Atherosclerosis Research Unit, Hôpital de la Pitié, Paris; Université Pierre and Marie Curie-Université de Paris, Unité Mixte de Recherche S551, Paris; and Assistance Publique-Hôpital de Paris, Groupe Hospitalier Pitié-Salpêtrière, Service d’Endocrinologie-Métabolisme, Paris, France

Impaired immune function and associated immunosuppression are hallmarks of septic syndromes. As part of an overall deactivation of the immune system, profound depletion of dendritic cells (DCs) occurs in both septic patients and septic mice. Such depletion of DCs is potentially associated with immunosuppression and with failure to induce a protective Th1 immune response; it may equally be predictive of fatal outcome in septic patients. To evaluate the impact of enhanced DC survival on LPS-induced immunosuppression and on survival after LPS-induced septic shock, we created a transgenic mouse model specifically overexpressing the human form of the antiapoptotic protein Bcl-2 in DCs (DC-hBcl-2 mice). DCs derived from DC-hBcl-2 mice exhibited higher resistance to maturation-induced apoptosis after LPS treatment both in vitro and in vivo. Moreover, prolongation of DC survival diminished sublethal LPS-induced DC loss and immunosuppression, with maintenance of the differentiation potential of Th1 cells and enhanced T cell activation. Such modulation of the immune response appears to constitute a key feature of the attenuated mortality observed after LPS-induced shock in DC-hBcl-2 mice. Our study therefore identifies DC death as a key determinant of endotoxin-induced immunosuppression and mortality in mice.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ E.L.G. was supported by a Fellowship from the Ministère de la Recherche and the Fondation pour la Recherche Médicale. This work was supported by Institut National de la Santé et de la Recherche Médicale and by an Award from the Fondation de France to P.L. M.J.C. and P.L. are the recipients of a Contrat d’Interface from the Assistance Publique-Hôpitaux de Paris/ Institut National de la Santé et de la Recherche Médicale.

² Address correspondence and reprint requests to Dr. Philippe Lesnik, INSERM U551, Hôpital de la Pitié, 83 Bd de l’hôpital, 75651 Paris 13, France. E-mail address: lesnik{at}chups.jussieu.fr

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived dendritic cell; Flt3-L, fms-like tyrosine kinase 3 ligand; PI, propidium iodide; WT, wild type.