Dendritic-cell genealogy

NEWS & VIEWSNATURE|Vol 462|10 December 2009Ahrens, T. J. Science 236, 181–182 (1987). 2. Catalli, K., Shim, S.-H. & Prakapenka, V. Nature 462, 782–785 (2009). 3. Murakami, M., Hirose, K., Kawamura, K., Sata, N. & Ohishi, Y. Science 304, 855–858 (2004). 4. Tsuchiya, T., Tsuchiya, J., Umemoto, K. & Wentzcovitch, R. M. Earth Planet. Sci. Lett. 224, 241–248 (2004). 5. Hernlund, J. W., Thomas, C. & Tackley, P. J. Nature 434, 882–886 (2005).6. Fei, Y. et al. Proc. Natl Acad. Sci. USA 104, 9182–9186 (2007). 7. Lay, T. Geophys. Res. Lett. doi:10.1029/2007gl032465 (2008). 8. Merkel, S. et al. Science 316, 1729–1732 (2007). 9. Wookey, J. & Kendall, J. M. in Post-Perovskite: The Last Mantle Phase Transition (eds Hirose, K., Brodholt, J., Lay, T. & Yuen, D.) 171–189 (Am. Geophys. Union, 2007). 10. Mao, W. L. et al. Science 312, 564–565 (2006).IMMUNOLOGYDendritic-cell genealogySophie Laffont and Fiona Powrie The differing origins of gut dendritic cells — white blood cells that modulate immune responses — may explain how the intestinal immune system manages to destroy harmful pathogens while tolerating beneficial bacteria.The immune system must protect the body from invading pathogens without mounting damaging responses to its own tissues. Dendritic cells, a rare population of white blood cells, have a crucial role in determining the nature of immune reactions and in fine-tuning the balance between tolerance (where theBacteriaimmune system ignores or tolerates an antigen) and the induction of inflammation to destroy pathogenic organisms. A long-standing question has been how dendritic cells drive these distinct immune outcomes. Two groups, Varol et al.1 and Bogunovic et al.2, report in Immunity that dendritic cells with distinctBacteria Epithelial cellIntestinal lumenMucosa CD103– CX3CR1+ DC CD103+ CX3CR1– DCTolerogenic responsesProtective immune responses Inflammatory t signals? Flt3 M-CSFPro-inflammatory mediatorsLymph nodesInflammatoryIncreased effector T-cell cell recruitment responsesBlood Pre-DC MonocyteBone marrow MDP Pre-DC MonocyteFigure 1 | Intestinal dendritic cells have different origins and different functions1,2. The two main subsets of intestinal dendritic cells (DCs) originate from distinct blood-cell precursors and depend on different growth factors for their development. Before this divergence, a common precursor, the macrophage and dendritic-cell precursor (MDP), gives rise to pre-dendritic cells (pre-DCs) and monocytes in the bone marrow. Pre-dendritic cells give rise to CD103+ CX3CR1– dendritic cells, and depend on the growth factor Flt3 for their development, whereas monocytes develop into CD103– CX3CR1+ dendritic cells, and depend on another growth factor, M-CSF. CD103+ dendritic cells transport microbial antigens to the lymph nodes, where they may initiate protective immune responses or promote the generation of regulatory T cells that help to maintain tolerance in the intestine. CX3CR1+ dendritic cells do not seem to migrate to lymph nodes, suggesting a more local role in promoting tissue inflammation by stimulating effector T-cell responses and producing pro-inflammatory mediators.732© 2009 Macmillan Publishers Limited. All rights reservedfunctions have different developmental origins, providing a cellular framework for the diverse activities of these cells. Pioneering work by Steinman and colleagues3 in the early 1970s identified a minor population of immune cells that they named dendritic cells on the basis of their stellate shape and membranous processes. These cells were shown to be potent stimulators of another population of white blood cells, T cells. Dendritic cells are strategically placed within mucosal sites in the body, where they can detect infection and take up microbial antigens. On activation, these cells migrate to secondary lymphoid tissue, such as the lymph nodes, where they present the antigen to T cells. This activates the T cells, causing them to differentiate into effector cells that eradicate the pathogen. In the intestine, dendritic cells also promote regulatory T-cell responses that suppress immune reactions against beneficial commensal bacteria and food antigens, thereby preventing immune-related disease. Thus, intestinal dendritic cells are decision makers, ensuring selection of a T-cell response that is appropriate to the nature of the challenge to the immune system. It is now known that dendritic cells are a diverse population of cells, differing in their anatomical location, expression of surface proteins and function. The diversity of the dendritic-cell response may reflect the differential activities of hard-wired developmentally distinct populations or may be due to different maturation states induced by environmental signals. Gaps in our knowledge of dendriticcell developmental pathways have hindered finding answers to these questions. However, recently developed genetic techniques4 to ablate dendritic-cell populations, together with an improved ability to identify specific dendritic-cell precursors, have advanced this area of research. Dendritic cells are closely related to macrophages, which originate from white blood cells called monocytes. They are derived from a common precursor termed the macrophage and dendritic-cell precursor (MDP). Dendritic cells can also be generated5 from monocytes in cell culture using a growth factor called granulocyte–macrophage colony-stimulating factor (GM-CSF), and much of what we know about the biology of dendritic cells has been based on the study of these laboratory-derived cells. However, recent elegant work6,7 has shown that monocytes and dendritic cells diverge in their developmental pathways downstream of the MDP — conventional dendritic cells in lymphoid tissue arise from a precursor cell in the blood (the pre-dendritic cell), and their differentiation depends on the growth factor Flt3. Hence, under normal conditions, blood monocytes do not give rise to dendritic cells in lymphoid tissue, raising questions about the in vivo counterpart of monocyte-derived dendritic cells. Varol et al.1 and Bogunovic et al.2 studied the development of dendritic cells in the intestine.NATURE|Vol 462|10 December 2009NEWS & VIEWSThese tissue dendritic cells can be identified by their expression of a surface protein, CD11c, and they can be divided further into two main subsets that express either of two surface proteins: CD103 or CX3CR1. Both studies1,2 show that CD103+ dendritic cells follow the same developmental pathway as conventional lymphoid dendritic cells: they arise from predendritic cells without a monocyte intermediate and depend on Flt3 for their development. By contrast, both groups1,2 find that monocytes give rise to intestinal CX3CR1+ dendritic cells (Fig. 1). Consistent with their origin from monocytes, these cells must express the macrophage growth-factor receptor known as macrophage-colony-stimulating factor (M-CSF) receptor in order to develop normally. Varol et al.1 also show that the GM-CSF receptor is required for monocyte-derived dendritic-cell development. However, Bogunovic and colleagues2 did not observe this dependence of monocyte-derived dendritic cells on GM-CSF, perhaps reflecting the use of different markers by the two groups1,2 to define the dendritic-cell populations. Why should the origins of intestinal dendritic cells differ from those of lymphoid dendritic cells? The answer may lie in the nature of the intestinal environment, which exists in a state of controlled inflammation, even in the absence of overt infection, because of continuous exposure to commensal bacteria. This controlled inflammatory state may be sufficient to recruit blood monocytes and induce their differentiation into dendritic cells locally. Importantly, pre-dendritic-cell and monocyte-derived dendritic-cell populations in the intestine have distinct functions (Fig. 1). CD103+ dendritic cells migrate from tissues, and can present ingested antigen to immune cells in the local intestinal lymph nodes (mesenteric lymph nodes). Under normal conditions, these CD103+ cells promote intestinal tolerance by inducing the generation of regulatory T cells8–10. But CD103+ dendritic cells can also activate CD8+ killer T cells and, through production of the vitamin A metabolite retinoic acid, induce the expression of receptors on T cells that direct them to the gut11. Consistent with these results, Bogunovic et al.2 show that CD103+ dendritic cells take up salmonella bacteria that have invaded the intestine and then transport the bacteria to mesenteric lymph nodes. Taken together, these data identify pre-dendritic-cell-derived CD103+ dendritic cells as important mediators of immune surveillance in the intestine that can promote both host-protective and tolerogenic T-cell responses. Monocyte-derived CX3CR1+ dendritic cells, on the other hand, have been associated with the induction of inflammatory T cells that promote intestinal inflammation12. CX3CR1+ dendritic cells have been shown to extend processes into the intestinal lumen to sample antigen. But Bogunovic et al.2 provide evidence that thesecells do not usually migrate to the mesenteric lymph nodes. Furthermore, Varol et al.1 demonstrate that CX3CR1+ dendritic cells alone are sufficient to drive intestinal inflammation by producing the pro-inflammatory mediator tumor necrosis factor-α. These observations raise the possibility that intestinal monocytederived dendritic cells do not initiate T-cell responses in secondary lymphoid tissue, but rather promote the inflammatory response at the site of pathogen entry. Further studies are required to assess the behaviour of this subset of dendritic cells during intestinal infection. The identification of the different progenitors of intestinal dendritic cells and the growth factors that control their development are crucial first steps to investigating the functional role of these distinct cell populations in health and disease. This important conceptual advance also potentially opens the door for targeted manipulation of dendritic-cell subsetsto treat immune-mediated diseases.■Sophie Laffont and Fiona Powrie are in the Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, and at the Sir William Dunn School of Pathology, Oxford, UK. e-mail: fiona.powrie@1. Varol, C. et al. Immunity 31, 502–512 (2009). 2. Bogunovic, M. et al. Immunity 31, 513–525 (2009). 3. Steinman, R. M. & Cohn, Z. A. J. Exp. Med. 137, 1142–1162 (1973). 4. Jung, S. et al. Immunity 17, 211–220 (2002). 5. Lutz, M. B. et al. J. Immunol. Methods 223, 77–92 (1999). 6. Waskow, C. et al. Nature Immunol. 9, 676–683 (2008). 7. Liu, K. et al. Science 324, 392–397 (2009). 8. Coombes, J. L. et al. J. Exp. Med. 204, 1757–1764 (2007). 9. Sun, C. M. et al. J. Exp. Med. 204, 1775–1785 (2007). 10. Jaensson, E. et al. J. Exp. Med. 205, 2139–2149 (2008). 11. Johansson-Lindbom, B. et al. J. Exp. Med. 202, 1063–1073 (2005). 12. Atarashi, K. et al. Nature 455, 808–812 (2008).STRUCTURAL BIOLOGYMolecular coin slots for ureaMark A. Knepper and Joseph A. Mindell Membrane-bound protein channels that allow only urea to pass through are vital to the kidney’s ability to conserve water. Crystal structures show that the channels select urea molecules by passing them through thin slots.Coin-operated vending machines must reliably accept only valid coins of the correct denomination. Modern machines recognize coins on the basis of their size, shape and even their chemical composition (determined by measuring the coins’ electromagnetic properties). On page 757 of this issue, Levin et al.1 describe the crystal structure of a bacterial urea-conducting channel that acts like a molecular version of a coin-operated machine — it selectively allows planar urea molecules to pass through on the basis of their size, shape and electrical-charge distribution. The authors’ results thereby provide insight into the function of a class of channel that is vital to the function of the human kidney. Urea is a small, nitrogen-containing organic molecule. Although uncharged, it is highly polar and adept at hydrogen bonding; indeed, urea’s ability to form hydrogen bonds with similarly polar water molecules accounts for its astonishingly high solubility in water (more than 8 M). Urea has a special place in the history of science, because it was the first organic molecule to be synthesized by non-biological means from inorganic starting materials2. It is also a key molecule in human physiology: in the liver, excess nitrogen from the normal breakdown of proteins is incorporated into urea, which is subsequently released into the bloodstream, ultimately to be excreted by the kidneys. Because of its high solubility and low© 2009 Macmillan Publishers Limited. All rights reservedtoxicity, large amounts of urea can be excreted in small amounts of water, allowing the kidney to conserve water even when urea excretion is high. But urea excretion presents a challenge for the kidney by virtue of the osmotic forces that the compound generates. The basic structural and functional unit of the kidney is the nephron. Each nephron filters water and small molecules (including urea) from the blood, creating a flow of fluid that passes through a long, narrow renal tubule. These tubules modify the filtered fluid using myriad transport processes, and what is left becomes urine. The final part of the renal tubule is called the collecting duct. Left uncontrolled, the osmotic force of the highly concentrated urea in collecting ducts would suck water from the kidney interstitium (the space between renal tubules), thus undesirably increasing water excretion, a process called osmotic diuresis (Fig. 1a, overleaf). To avoid this, the kidney must balance urea concentrations inside and outside the urinary space by allowing urea to move rapidly across the membranes of the epithelial cells that line the collecting duct (Fig. 1b). The polarity of urea molecules prevents them from readily penetrating nonpolar lipid membranes. Kidney cells therefore use specialized channel proteins to move the molecule rapidly into and through cells. These channels — called UT-A1 and UT-A3 — allow urea733。