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T Cell-Dependent Activation of Dendritic Cells Requires IL-12 and IFN- Signaling in T Cells¹

Francesc Miro^*, Cinzia Nobile^*, Nicolas Blanchard^*, Marianne Lind^*, Orchidée Filipe-Santos, Claire Fieschi, Ariane Chapgier, Guillaume Vogt, Ludovic de Beaucoudrey, Dinakantha S. Kumararatne, Françoise Le Deist, Jean-Laurent Casanova, Sebastian Amigorena^* and Claire Hivroz^2,*

^* Institut National de la Santé et de la Recherche Médicale Unité 653, Institut Curie, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale Unité 550, Necker-Enfants Malades Medical School, Paris, France; Medical Research Council Center for Immune Regulation, The Medical School, University of Birmingham, Edgbaston, Birmingham, United Kingdom; and Institut National de la Santé et de la Recherche Médicale Unité 429, Hôpital Necker-Enfants Malades, Paris, France

Patients presenting with genetic deficiencies in IFNGR1, IFNGR2, IL-12B, and IL-12RB1 display increased susceptibility to mycobacterial infections. We analyzed in this group of patients the cross-talk between human CD4⁺ T lymphocytes and dendritic cells (DCs) that leads to maturation of DC into producers of bioactive IL-12 and to activation of T cells into IFN- producers. We found that this cross-talk is defective in all patients from this group. Unraveling the mechanisms underlying this deficiency, we showed that IL-12 signaling in T cells is required to induce expression of costimulatory molecules and secretion of IL-12 by DCs and that IFNGR expression is required on both DCs and CD4⁺ T cells to induce IL-12 secretion by DCs. These data suggest that CD4⁺ T cell-mediated activation of DCs plays a critical role in the defense against mycobacterial infections in humans.

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 financially supported by Institut National de la Santé et de la Recherche Médicale, Institut Curie, and Association pour la Recherche Contre le Cancer. F.M. is the recipient of a grant from Association pour la Recherche Contre le Cancer.

² Address correspondence and reprint requests to Dr. Claire Hivroz, Institut National de la Santé et de la Recherche Médicale Unité 653, Institut Curie, 26, Rue d’Ulm, 75248 Paris Cedex 05, France. E-mail address: claire.hivroz{at}curie.fr

³ Abbreviations used in this paper: BCG, bacille Calmette-Guérin; DC, dendritic cell; TSST1, toxic shock syndrome toxin 1; WT, wild type.

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