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Regulatory T Cells Control Dendritic Cell/NK Cell Cross-Talk in Lymph Nodes at the Steady State by Inhibiting CD4⁺ Self-Reactive T Cells

Magali Terme^1,*, Nathalie Chaput^1,*,, Behazine Combadiere, Averil Ma^¶, Toshiaki Ohteki^|| and Laurence Zitvogel^2,*,,

^* Institut National de la Santé et de la Recherche Médicale Unité 805, Tumor Immunology and Immunotherapy and Centre d’Investigation Clinique Biothérapie, Institut Gustave Roussy, Villejuif, France; Institut National de la Santé et de la Recherche Médicale Unité 543, Université Pierre et Marie Curie-Paris6, Laboratoire d’Immunologie Cellulaire, Hôpital Pitié Salpétrière, Paris, France; Faculté de Médecine, Université Paris Sud Paris XI, Kremlin Bicêtre, France; ^¶ Department of Medicine, University of California, San Francisco, CA 94143; and ^|| Department of Immunology, Akita University Graduate School of Medicine, Akita-city, Japan

The CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Treg) play an important role in the control of peripheral tolerance by directly inhibiting conventional T cell proliferative and effector functions. However, the mechanisms by which Treg regulate the homeostasis of lymph nodes remain unclear. In this study, we show in a mouse model that Treg control two major checkpoints dictated by the interaction between self-reactive CD4⁺ T cells and resident dendritic cell (DC) in secondary lymphoid organs. First, Treg inhibit the production of CCR5 ligands, limiting the CCR5-dependent recruitment of DC in the lymph nodes. Second, Treg prevent the DC exposure of IL-15R, markedly interfering in the DC-mediated NK cell proliferation in vivo. Therefore, the DC/T cell autoreactivity leading to NK cell triggering could potentially be controlled by the coinhibition of both IL-15R and CCR5 in autoimmune disorders in which NK cells play a deleterious role.

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 M.T. and N.C. contributed equally to this work.

² Address correspondence and reprint requests to Prof. Laurence Zitvogel, Institut National de la Santé et de la Recherche Médicale Unité 805, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. E-mail address: zitvogel{at}igr.fr

³ Abbreviations used in this paper: Treg, regulatory T cell; DC, dendritic cell; CTX, cyclophosphamide; LN, lymph node; WT, wild type; Tconv, conventional T cell; BM-DC, bone marrow-derived DC; DT, diphtheria toxin; DTX, DT receptor.