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* Immunology Laboratory, Hôpital Neurologique, Hospices Civils de Lyon, Lyon, France;
Joint Unit bioMérieux, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France;
Lyon-Sud University Hospital, Immunology Laboratory, Hospices Civils de Lyon, Pierre-Bénite, France;
Intensive Care Units, Lyon-Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, France; and
¶ Meakins-Christie Laboratories, McGill University, Montreal, Canada
Although it is known that septic shock induces immunosuppression, the mechanism for this phenomenon is not well understood. Monocytes play a central role in septic shock pathophysiology, which is also characterized by an increased proportion of natural regulatory T (Treg) cells. We therefore investigated whether Treg could be involved in the decreased monocyte expression of CD14 and HLA-DR observed during septic shock. We demonstrated that human Treg inhibit LPS-induced retention of monocyte CD14. Because loss of CD14 is a hallmark of monocyte apoptosis, this suggests that Treg inhibit monocyte survival. This effect was largely mediated through the release of a soluble mediator that was not identical with either IL-10 or IL-4. The Fas/FasL pathway participated in the effect as it was blocked by anti-FasL Abs and reproduced by Fas agonist and recombinant soluble FasL. Furthermore, expression of FasL was much higher on Treg than on their CD25– counterparts. Collectively, these results indicate that Treg act on monocytes by inhibiting their LPS-induced survival through a proapoptotic mechanism involving the Fas/FasL pathway. This may be an important mechanism for septic shock-induced immunosuppression and may offer new perspectives for the treatment of this deadly disease.
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 This work was supported by grants from the Hospices Civils de Lyon (médaille d’or de l’internat) (to F.V.) and the Canadian Institutes of Health Research (to W.S.P.).
2 Address correspondence and reprint requests to Dr. G. Monneret, Flow Cytometry Unit-Immunology Laboratory, Hôpital Neurologique, Hospices Civils de Lyon, 59 Boulevard Pinel, 69677 Bron Cedex, France. E-mail address: guillaume.monneret{at}chu-lyon.fr
3 Abbreviations used in this paper: Treg, regulatory T cell; DIOC-6, 3,3'-dihexyloxacarbocyanine iodide.
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