The Axis of Tolerance Tegest Aychek and Steffen Jung Science 343, 1439 (2014); DOI: 10.1126/science.1252785
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here. Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of March 31, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/343/6178/1439.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/343/6178/1439.full.html#related This article cites 11 articles, 4 of which can be accessed free: http://www.sciencemag.org/content/343/6178/1439.full.html#ref-list-1 This article appears in the following subject collections: Immunology http://www.sciencemag.org/cgi/collection/immunology
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on March 31, 2014
This copy is for your personal, non-commercial use only.
PERSPECTIVES IMMUNOLOGY
Communication between different immune cells of the intestinal mucosa acts as a rheostat that maintains tolerance to gut microbes.
The Axis of Tolerance Tegest Aychek and Steffen Jung
Steady-state communication. Upon sensing Commensal he gut poses a unique challenge microbial products in the gut, macrophages bacteria to the organism. The host must secrete IL-1β, which triggers innate lymphoid tolerate beneficial commencells (ILC3s) to produce Csf2. Csf2-exposed DCs sal bacteria, yet allow for rapid proIntestinal release retinoic acid, which promotes the genStimuli epithelial Microbial tective responses to invading pathoeration of Tregs. Csf2 also increases the number cells product gens. Failure to maintain this balance of macrophages and induces them to release may cause intestinal disorders such as IL-10, which might contribute to local effector chronic inflammatory bowel disease. T cell maintenance. Sensor Fortunately, a dynamic, yet robust, state of chronic, low-grade inflammaMortha et al. identify an intriguing tion maintains this balance (“primed microbiota-triggered steady-state crossMacrophage homeostasis”). Thus, the host actively talk between intestinal mononuclear engages the gut microbiota, controlling phagocytes (macrophages and DCs) its composition by secreting antimicroand ILCs that act as a rheostat for gut bial peptides and immunoglobulins. mucosal adaptive immunity. The core Conversely, commensals shape the of this cellular circuit consists of macIL-1β gut-associated immune system by conrophages acting as microbiota sensors, trolling the prevalence of distinct T cell and ILC3s that modulate the size and populations (1). On page 1477 of this functionality of the DC compartment issue, Mortha et al. (2) show how comby secreting colony-stimulating factor ILC3 munication between specific myeloid Rheostat 2 (Csf2; also called granulocyte-macrocells and lymphoid cells controls immune phage colony-stimulating factor). Csf2 homeostasis under exposure to the gut stimulates the growth and differentiaCsf2 microflora. Such cellular details of this tion of mononuclear phagocytes. The steady state may guide the developimpact on DCs ultimately affects adapment of rational therapies for intestinal tive T cell immune responses (see the Dendritic cells Effector inflammatory conditions. figure). The authors observed that Csf2 Intestinal macrophages are strateproduction by ILC3s was impaired in Retinoic acid gically positioned below the intestinal mice whose macrophages were either epithelium and highly abundant in the transiently depleted or rendered unrelamina propria (3), where they engulf sponsive to microbial stimuli. ImporT reg Effector cellular debris. Whereas most other tantly, Csf2 production in these anicells tissue macrophages are established mals could be restored by exogenous prenatally and maintained throughIL-1β, suggesting that this “proinflamOutput Homeostasis out adulthood by longevity and limmatory” cytokine is key to the macroited self-renewal (4, 5), these cells disphage–ILC crosstalk. Indeed, ILC3s of play—in keeping with their rapidly changing and by this means, determine host resistance mice lacking the receptor for IL-1β failed to surroundings and tonic mild inflammation—a to pathogen challenges. More recently, innate produce Csf2. Thus, microbe-sensing, inteshigh steady-state turnover in the gut. Intesti- lymphoid cells (ILCs) have been shown to play tinal steady-state macrophages secrete IL-1β nal macrophages are continuously renewed a key role in gut homeostasis. These cells lack to induce the release of Csf2 by ILC3s, highfrom monocytes that are recruited from blood antigen receptors and their activities are trig- lighting the recruitment of proinflammatory and differentiate in the healthy gut into nonin- gered by cytokines derived from neighboring factors for maintaining gut homeostasis. flammatory cells (6). Timely conditioning of cells. Gut ILCs promote the formation of isoUnlike the growth-promoting activity of monocytes to adopt specific gene expression lated lymphoid follicles, structures that sup- Csf2 on cultured cells, its functions in anisignatures allows them to help maintain local port “homeostatic” immune responses. A sub- mals have long remained enigmatic. Csf2 is tissue homeostasis. Intestinal dendritic cells set of ILCs [in which the transcription factor a key effector molecule produced by TH17 (DCs), by contrast, can efficiently migrate retinoic acid receptor–related orphan receptor cells that sustains inflammation induced by to lymph nodes, thereby providing a critical gamma t (RORγ t) functions in development] experimental autoimmune encephalomyelilink to adaptive T cell immunity (7). Gut DCs called RORγt-dependent group 3 innate lym- tis (8, 9). Unexpectedly, however, Csf2 is disgovern the intestinal prevalence of T helper phoid cells (ILC3s), maintains the intestinal pensable for the development of proinflam17 (TH17), TH1, and T regulatory (Treg) cells, epithelial barrier by secreting the cytokine matory DCs derived from monocytes (10). interleukin-22 (IL-22), which has an important Rather, Csf2 promotes nonlymphoid tissue role in protecting the intestinal epithelium fol- DC homeostasis (10). The finding that ILC3s Department of Immunology, The Weizmann Institute of Scilowing injury or infection by pathogens. are a key steady-state source of Csf2 in lowence, Rehovot 76100, Israel. E-mail: [email protected]
CREDIT: V. ALTOUNIAN/SCIENCE
T
www.sciencemag.org SCIENCE VOL 343 28 MARCH 2014 Published by AAAS
1439
PERSPECTIVES grade “physiological inflammation” in the gut adds an intriguing new twist to this puzzle. Moreover, Mortha et al. show that Csf2 controls not only the amount of intestinal DCs, but also their functions. Specifically, DCs, as well as macrophages, isolated from mice lacking Csf2 displayed impaired expression of retinaldehyde dehydrogenase, the enzyme that generates retinoic acid. As a consequence, these DCs failed to support the generation of Tregs in ex vivo cultures—a defect that could be restored by addition of Csf2. The functional deficiency of these cells also translated into a general reduction in the number of colonic Treg cells and an impaired in vivo generation of Tregs in a mucosal tolerance paradigm (oral tolerance to dietary antigens), both in mice deficient in Csf2 production as well as in animals specifically lacking ILC3s that produce Csf2. These findings establish Csf2 production by ILC3 as a critical steady-state rheostat for adjusting intestinal T cell immunity to the microbiota status. Notably, retinoic acid is also critical for the imprinting of gut homing of effector T cells and thus represents a central factor in gut homeostasis.
Csf2-producing ILC3s are concentrated in isolated lymphoid follicles, but it is unclear whether these structures provide a unique permissive environment or if the macrophage–ILC-DC axis operates throughout the lamina propria. Mortha et al. show that antibiotic treatment of mice reduces Csf2 production by ILC3s. Although this treatment reduces the commensal load, it also creates profound dysbiosis. Do specific bacterial species activate the macrophages, and might this explain why these cells are equipped with transepithelial dendrites to sense the gut lumen (11)? With macrophage sensors and DCs that relay information to T cells, Mortha et al. emphasize the dual role of mononuclear phagocytes in gut homeostasis. However, differential functions of macrophages and DC subsets in this context remain incompletely understood. Of note, special activities of these cells are probably overridden in cell cultures, which neglect restraints imposed by discrete location and an in vivo requirement for migration. The findings of Mortha et al., if translatable into the human setting, could have
major implications in the clinic. Impairments of Csf2 signaling, either due to ligand neutralization by autoantibodies or receptor mutations, have been associated with deteriorating intestinal bowel disease. However, clinical trials of this disorder with Csf2, performed under the assumption that it boosts immunity, so far have failed to yield conclusive benefit. The study of Mortha et al. suggests a more complex role of Csf2 in the pathology of this condition. Success of Csf2 therapy in inflammatory bowel disease will, hence, likely depend on the right choice of patients and personalization of treatments. References 1. I. I. Ivanov, K. Honda, Cell Host Microbe 12, 496 (2012). 2. A. Mortha et al., Science 342, 1249288 (2014); 10.1126/science.1249288. 3. E. Zigmond, S. Jung, Trends Immunol. 34, 162 (2013). 4. C. Schulz et al., Science 336, 86 (2012). 5. S. Yona et al., Immunity 38, 79 (2013). 6. E. Zigmond et al., Immunity 37, 1076 (2012). 7. T. Worbs et al., J. Exp. Med. 203, 519 (2006). 8. L. Codarri et al., Nat. Immunol. 12, 560 (2011). 9. M. El-Behi et al., Nat. Immunol. 12, 568 (2011). 10. M. Greter et al., Immunity 36, 1031 (2012). 11. J. H. Niess et al., Science 307, 254 (2005). 10.1126/science.1252785
ASTRONOMY
A Different Class of Planets
Detection of a carbon dioxide gas cloud suggests the presence of an exoplanet further out from its host star than usual.
Alexis Brandeker
E
verywhere we look, it seems, we find exoplanets—planets orbiting stars other than the Sun. It is now estimated that, on average, there is at least one planet for every solar-type star (1). The vast majority (>98%) of known exoplanets have been found not through direct imaging, but by careful observation of how the host star is influenced by the presence of a planet; whether by induced motion from gravity or a periodic occultation of the stellar light. These indirect methods are heavily biased toward finding planets near their star, as those are the planets that influence the star the most. On page 1490 of this issue, Dent et al. (2) present results that implicate a planet far out from its star, through a technique that links the location of CO gas in the disk around a young star to the influence of an unseen planet. Disk structures induced by planets are not limited to regions near the star, so even planets in wide orbits around their star are detectDepartment of Astronomy, Stockholm University, AlbaNova University Center, Stockholm, 106 91 Sweden. E-mail: [email protected]
1440
able in this way. The challenge is that disks are faint, generally difficult to resolve, and are common only around young stars. It is thus not surprising that the system that Dent et al. choose to study is β Pictoris (β Pic), a young (~20 million years old), nearby (~20 pc) star harboring one of the brightest and largest disks known; indeed, the disk around β Pic was the first ever to be imaged (3), an occasion that this year marks its 30th anniversary. Moreover, from previous observations, a massive super-Jupiter called β Pic b is known to orbit the star at ~10 astronomical units (AU) (1 AU is the distance between Earth and the Sun). The planet was first inferred from its gravitational influence, by the massive warp of the inner disk that was observed in light scattered off dust grains (4). It took more than a decade before β Pic b was directly imaged and seen to orbit the star (5). Dent et al. observe a clump of CO at 85 AU from the star. Because CO does not survive for long in the ultraviolet field from neighboring stars, the implication is that the CO must be currently produced, perhaps by the destruction of icy bodies through enhanced colli-
28 MARCH 2014 VOL 343
sions in this particular region. The enhanced rate of collisions could be due to either a Neptune-sized or larger planet in a wide, 60-AU orbit (twice the orbital size of “our” Neptune), or a relatively recent (
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here. Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of March 31, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/343/6178/1439.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/343/6178/1439.full.html#related This article cites 11 articles, 4 of which can be accessed free: http://www.sciencemag.org/content/343/6178/1439.full.html#ref-list-1 This article appears in the following subject collections: Immunology http://www.sciencemag.org/cgi/collection/immunology
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on March 31, 2014
This copy is for your personal, non-commercial use only.
PERSPECTIVES IMMUNOLOGY
Communication between different immune cells of the intestinal mucosa acts as a rheostat that maintains tolerance to gut microbes.
The Axis of Tolerance Tegest Aychek and Steffen Jung
Steady-state communication. Upon sensing Commensal he gut poses a unique challenge microbial products in the gut, macrophages bacteria to the organism. The host must secrete IL-1β, which triggers innate lymphoid tolerate beneficial commencells (ILC3s) to produce Csf2. Csf2-exposed DCs sal bacteria, yet allow for rapid proIntestinal release retinoic acid, which promotes the genStimuli epithelial Microbial tective responses to invading pathoeration of Tregs. Csf2 also increases the number cells product gens. Failure to maintain this balance of macrophages and induces them to release may cause intestinal disorders such as IL-10, which might contribute to local effector chronic inflammatory bowel disease. T cell maintenance. Sensor Fortunately, a dynamic, yet robust, state of chronic, low-grade inflammaMortha et al. identify an intriguing tion maintains this balance (“primed microbiota-triggered steady-state crossMacrophage homeostasis”). Thus, the host actively talk between intestinal mononuclear engages the gut microbiota, controlling phagocytes (macrophages and DCs) its composition by secreting antimicroand ILCs that act as a rheostat for gut bial peptides and immunoglobulins. mucosal adaptive immunity. The core Conversely, commensals shape the of this cellular circuit consists of macIL-1β gut-associated immune system by conrophages acting as microbiota sensors, trolling the prevalence of distinct T cell and ILC3s that modulate the size and populations (1). On page 1477 of this functionality of the DC compartment issue, Mortha et al. (2) show how comby secreting colony-stimulating factor ILC3 munication between specific myeloid Rheostat 2 (Csf2; also called granulocyte-macrocells and lymphoid cells controls immune phage colony-stimulating factor). Csf2 homeostasis under exposure to the gut stimulates the growth and differentiaCsf2 microflora. Such cellular details of this tion of mononuclear phagocytes. The steady state may guide the developimpact on DCs ultimately affects adapment of rational therapies for intestinal tive T cell immune responses (see the Dendritic cells Effector inflammatory conditions. figure). The authors observed that Csf2 Intestinal macrophages are strateproduction by ILC3s was impaired in Retinoic acid gically positioned below the intestinal mice whose macrophages were either epithelium and highly abundant in the transiently depleted or rendered unrelamina propria (3), where they engulf sponsive to microbial stimuli. ImporT reg Effector cellular debris. Whereas most other tantly, Csf2 production in these anicells tissue macrophages are established mals could be restored by exogenous prenatally and maintained throughIL-1β, suggesting that this “proinflamOutput Homeostasis out adulthood by longevity and limmatory” cytokine is key to the macroited self-renewal (4, 5), these cells disphage–ILC crosstalk. Indeed, ILC3s of play—in keeping with their rapidly changing and by this means, determine host resistance mice lacking the receptor for IL-1β failed to surroundings and tonic mild inflammation—a to pathogen challenges. More recently, innate produce Csf2. Thus, microbe-sensing, inteshigh steady-state turnover in the gut. Intesti- lymphoid cells (ILCs) have been shown to play tinal steady-state macrophages secrete IL-1β nal macrophages are continuously renewed a key role in gut homeostasis. These cells lack to induce the release of Csf2 by ILC3s, highfrom monocytes that are recruited from blood antigen receptors and their activities are trig- lighting the recruitment of proinflammatory and differentiate in the healthy gut into nonin- gered by cytokines derived from neighboring factors for maintaining gut homeostasis. flammatory cells (6). Timely conditioning of cells. Gut ILCs promote the formation of isoUnlike the growth-promoting activity of monocytes to adopt specific gene expression lated lymphoid follicles, structures that sup- Csf2 on cultured cells, its functions in anisignatures allows them to help maintain local port “homeostatic” immune responses. A sub- mals have long remained enigmatic. Csf2 is tissue homeostasis. Intestinal dendritic cells set of ILCs [in which the transcription factor a key effector molecule produced by TH17 (DCs), by contrast, can efficiently migrate retinoic acid receptor–related orphan receptor cells that sustains inflammation induced by to lymph nodes, thereby providing a critical gamma t (RORγ t) functions in development] experimental autoimmune encephalomyelilink to adaptive T cell immunity (7). Gut DCs called RORγt-dependent group 3 innate lym- tis (8, 9). Unexpectedly, however, Csf2 is disgovern the intestinal prevalence of T helper phoid cells (ILC3s), maintains the intestinal pensable for the development of proinflam17 (TH17), TH1, and T regulatory (Treg) cells, epithelial barrier by secreting the cytokine matory DCs derived from monocytes (10). interleukin-22 (IL-22), which has an important Rather, Csf2 promotes nonlymphoid tissue role in protecting the intestinal epithelium fol- DC homeostasis (10). The finding that ILC3s Department of Immunology, The Weizmann Institute of Scilowing injury or infection by pathogens. are a key steady-state source of Csf2 in lowence, Rehovot 76100, Israel. E-mail: [email protected]
CREDIT: V. ALTOUNIAN/SCIENCE
T
www.sciencemag.org SCIENCE VOL 343 28 MARCH 2014 Published by AAAS
1439
PERSPECTIVES grade “physiological inflammation” in the gut adds an intriguing new twist to this puzzle. Moreover, Mortha et al. show that Csf2 controls not only the amount of intestinal DCs, but also their functions. Specifically, DCs, as well as macrophages, isolated from mice lacking Csf2 displayed impaired expression of retinaldehyde dehydrogenase, the enzyme that generates retinoic acid. As a consequence, these DCs failed to support the generation of Tregs in ex vivo cultures—a defect that could be restored by addition of Csf2. The functional deficiency of these cells also translated into a general reduction in the number of colonic Treg cells and an impaired in vivo generation of Tregs in a mucosal tolerance paradigm (oral tolerance to dietary antigens), both in mice deficient in Csf2 production as well as in animals specifically lacking ILC3s that produce Csf2. These findings establish Csf2 production by ILC3 as a critical steady-state rheostat for adjusting intestinal T cell immunity to the microbiota status. Notably, retinoic acid is also critical for the imprinting of gut homing of effector T cells and thus represents a central factor in gut homeostasis.
Csf2-producing ILC3s are concentrated in isolated lymphoid follicles, but it is unclear whether these structures provide a unique permissive environment or if the macrophage–ILC-DC axis operates throughout the lamina propria. Mortha et al. show that antibiotic treatment of mice reduces Csf2 production by ILC3s. Although this treatment reduces the commensal load, it also creates profound dysbiosis. Do specific bacterial species activate the macrophages, and might this explain why these cells are equipped with transepithelial dendrites to sense the gut lumen (11)? With macrophage sensors and DCs that relay information to T cells, Mortha et al. emphasize the dual role of mononuclear phagocytes in gut homeostasis. However, differential functions of macrophages and DC subsets in this context remain incompletely understood. Of note, special activities of these cells are probably overridden in cell cultures, which neglect restraints imposed by discrete location and an in vivo requirement for migration. The findings of Mortha et al., if translatable into the human setting, could have
major implications in the clinic. Impairments of Csf2 signaling, either due to ligand neutralization by autoantibodies or receptor mutations, have been associated with deteriorating intestinal bowel disease. However, clinical trials of this disorder with Csf2, performed under the assumption that it boosts immunity, so far have failed to yield conclusive benefit. The study of Mortha et al. suggests a more complex role of Csf2 in the pathology of this condition. Success of Csf2 therapy in inflammatory bowel disease will, hence, likely depend on the right choice of patients and personalization of treatments. References 1. I. I. Ivanov, K. Honda, Cell Host Microbe 12, 496 (2012). 2. A. Mortha et al., Science 342, 1249288 (2014); 10.1126/science.1249288. 3. E. Zigmond, S. Jung, Trends Immunol. 34, 162 (2013). 4. C. Schulz et al., Science 336, 86 (2012). 5. S. Yona et al., Immunity 38, 79 (2013). 6. E. Zigmond et al., Immunity 37, 1076 (2012). 7. T. Worbs et al., J. Exp. Med. 203, 519 (2006). 8. L. Codarri et al., Nat. Immunol. 12, 560 (2011). 9. M. El-Behi et al., Nat. Immunol. 12, 568 (2011). 10. M. Greter et al., Immunity 36, 1031 (2012). 11. J. H. Niess et al., Science 307, 254 (2005). 10.1126/science.1252785
ASTRONOMY
A Different Class of Planets
Detection of a carbon dioxide gas cloud suggests the presence of an exoplanet further out from its host star than usual.
Alexis Brandeker
E
verywhere we look, it seems, we find exoplanets—planets orbiting stars other than the Sun. It is now estimated that, on average, there is at least one planet for every solar-type star (1). The vast majority (>98%) of known exoplanets have been found not through direct imaging, but by careful observation of how the host star is influenced by the presence of a planet; whether by induced motion from gravity or a periodic occultation of the stellar light. These indirect methods are heavily biased toward finding planets near their star, as those are the planets that influence the star the most. On page 1490 of this issue, Dent et al. (2) present results that implicate a planet far out from its star, through a technique that links the location of CO gas in the disk around a young star to the influence of an unseen planet. Disk structures induced by planets are not limited to regions near the star, so even planets in wide orbits around their star are detectDepartment of Astronomy, Stockholm University, AlbaNova University Center, Stockholm, 106 91 Sweden. E-mail: [email protected]
1440
able in this way. The challenge is that disks are faint, generally difficult to resolve, and are common only around young stars. It is thus not surprising that the system that Dent et al. choose to study is β Pictoris (β Pic), a young (~20 million years old), nearby (~20 pc) star harboring one of the brightest and largest disks known; indeed, the disk around β Pic was the first ever to be imaged (3), an occasion that this year marks its 30th anniversary. Moreover, from previous observations, a massive super-Jupiter called β Pic b is known to orbit the star at ~10 astronomical units (AU) (1 AU is the distance between Earth and the Sun). The planet was first inferred from its gravitational influence, by the massive warp of the inner disk that was observed in light scattered off dust grains (4). It took more than a decade before β Pic b was directly imaged and seen to orbit the star (5). Dent et al. observe a clump of CO at 85 AU from the star. Because CO does not survive for long in the ultraviolet field from neighboring stars, the implication is that the CO must be currently produced, perhaps by the destruction of icy bodies through enhanced colli-
28 MARCH 2014 VOL 343
sions in this particular region. The enhanced rate of collisions could be due to either a Neptune-sized or larger planet in a wide, 60-AU orbit (twice the orbital size of “our” Neptune), or a relatively recent (
