The Journal of Experimental Medicine ARTICLE JEM © The Rockefeller University Press $15.00 Vol. 204, No. 6, June 11, 2007 1487–1501 www.jem.org/cgi/doi/10.1084/jem.20070325 1487 The ability to respond rapidly to invading patho- gens is a prerequisite for efective immunity to infection. Many immune and nonimmune cells are equipped with specialized pattern-recogni- tion receptors (PRRs), such as the vertebrate Toll-like receptors (TLRs), which allow them to sense a large variety of pathogen-associated molecular patterns (PAMPs) and initiate an in- lammatory response (1, 2). In all organisms, the innate inlammatory response initiated by PRRs is essential to contain immediate pathogen spread and to promote tissue repair (3). But, in verte- brates, PRRs can additionally act to promote DC activation and translation of innate into adaptive immunity (4–6). DCs are bone marrow–derived cells scattered throughout lymphoid and non- lymphoid organs, where they act as immune sentinels by responding to invading pathogens (4–6). Direct stimulation of DCs via TLRs and some other classes of PRRs induces their transi- tion from resting cells into an “activated” efec- tor state in which they can direct the expansion and diferentiation of naive T cells into efectors (4–7).This process is accompanied by processing and presentation of pathogen-derived material, up-regulation of co-stimulatory molecules, mi- gration of DCs to the T cell areas of secondary lymphoid organs, and production of cytokines and chemokines, all of which are important for selecting and priming rare naive, pathogen-speciic T cells (7).Thus, stimulation of DCs through their PRRs allows the coupling of an immediate, pro- tective innate response to an antigen-speciic and long-lasting adaptive response. Inlammation can also be triggered in sterile conditions, arguing for the existence of PAMP- independent pathways of innate response. Some triggers, such as genomic DNA or self-RNA– protein complexes, appear to act only in patho- logical conditions, by mimicking viral PAMPs and triggering PRRs involved in antiviral de- fense (8).They may, therefore, not be representa- tive of DC responsiveness to infection. However, other endogenous triggers have been proposed Dendritic cell quiescence during systemic inlammation driven by LPS stimulation of radioresistant cells in vivo Martijn A. Nolte, Salomé LeibundGut-Landmann, Olivier Jofre, and Caetano Reis e Sousa Immunobiology Laboratory, Cancer Research UK, London Research Institute, Lincoln’s Inn Fields Laboratories, London WC2A 3PX, England, UK Dendritic cell (DC) activation is a prerequisite for T cell priming. During infection, activation can ensue from signaling via pattern-recognition receptors after contact with pathogens or infected cells. Alternatively, it has been proposed that DCs can be activated indirectly by signals produced by infected tissues. To address the contribution of tissue-derived signals, we measured DC activation in a model in which radioresistant cells can or cannot respond to lipopolysaccharide (LPS). We report that recognition of LPS by the radioresistant com- partment is suficient to induce local and systemic inlammation characterized by high circulating levels of tumor necrosis factor (TNF) α, interleukin (IL) 1β, IL-6, and CC chemo- kine ligand 2. However, this is not suficient to activate DCs, whether measured by migra- tion, gene expression, phenotypic, or functional criteria, or to render DC refractory to subsequent stimulation with CpG-containing DNA. Similarly, acute or chronic exposure to proinlammatory cytokines such as TNF-α ± interferon α/β has marginal effects on DC phenotype in vivo when compared with LPS. In addition, DC activation and migration induced by LPS is unimpaired when radioresistant cells cannot respond to the stimulus. Thus, inlammatory mediators originating from nonhematopoietic tissues and from radioresistant hematopoietic cells are neither suficient nor required for DC activation in vivo. CORRESPONDENCE Caetano Reis e Sousa: caetano@cancer.org.uk Abbreviations used: ARE, AU-rich elements; CCL, CC chemokine ligand; CCR, CC chemokine receptor; CXCL, CXC chemokine ligand; GeoMFI, geometric mean luor- escence intensity; PALS, peri- arteriolar lymphatic sheath; PAMP, pathogen-associated molecular pattern; PRR, pattern-recognition receptor; SOCS, suppressor of cytokine signaling; TLR, Toll- like receptor. M.A. Nolte’s present address is Dept. of Experimental Immunology, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands. The online version of this article contains supplemental material.