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6. Mucida, D. et al. Nat. Immunol. 14, 281–289 (2013). 9. egawa, T. & Littman, D.R. Nat. Immunol. 9, 11. Steinke, F.C. et al. Nat. Immunol. 15, 646–656 7. Reis, B.S. et al. Nat. Immunol. 14, 271–280 (2013). 1131–1139 (2008). (2014). 8. Honda, K. & Littman, D.R. Annu. Rev. Immunol. 30, 10. Muroi, S. et al. Nat. Immunol. 9, 1113–1121 12. Luckey, M.A. et al. Nat. Immunol. 15, 638–645 759–795 (2012). (2008). (2014). worm their way into macrophage long- term memory

John R Grainger & Richard K Grencis function is perhaps best studied in bacterial infection, during which they are directly involved in killing. After helminth invasion, however, neutrophils acquire an alternative transcriptional profile that allows them to ‘train’ macrophages to acquire long-term protective features.

elminth infections affect almost 2 bil- along with their production of a plethora of expression of integrin αM (CD11b) is increased Hlion people worldwide, particularly in bactericidal factors, including reactive on macrophages following primary infection the developing world, and are a major cause species, elastase and neutrophil extracellular with N. brasiliensis and, using an in vitro larval of morbidity. Their high prevalence results traps (NETs)3. The recruitment of neutrophils killing assay, the authors show that this integrin is in part from poor development of protective is not limited to bacterial infection, however, important in augmenting macrophage-mediated despite ongoing exposure to these as they swiftly transit to the site of pathogen killing4. Unexpectedly, upregulation of the infections. Better understanding of the mech- entry in response to various types of invader, expression of arginase-1 and CD11b on lung mac- anisms that contribute to long-term protec- including helminths2,5,6. Although they may rophages, and hence secondary protection against tion is crucial for establishing more targeted serve a direct role in killing larvae, one possi- the helminth, is critically dependent on the pres- approaches to deal with disease and support bility is that here too their dominant function ence of neutrophils during primary infection. In vaccine development. Although rodent models is protection against , as helminths can agreement with those findings, sorted lung mac- of hookworm infection have been used to study carry bacteria into tissues as a result of barrier rophages from mice infected with N. brasiliensis secondary protection since the early 1900s1, breach during invasion2,6. but depleted of neutrophils are unable to mediate understanding of the cell types that contrib- A less-well-explored aspect of neutrophil protection against helminth challenge following ute to this protection and the tissue-specific function is their ability to influence the function intravenous transfer into naive hosts, unlike mac- mechanisms involved are still poorly under- of cell populations with which they are closely rophages from control mice infected similarly but stood. The protective ability of localized during infection, such as - treated with -matched control . populations, including , macrophages. Perhaps the best described exam- The ability of neutrophils to ‘train’ lung and mast cells, has been well studied in infec- ple of neutrophils’ modulating macrophage macrophages is associated with their acquisi- Nature America, Inc. All rights reserved. America, Inc. © 201 4 Nature tion with various helminths2. Whether neutro- function is the uptake of apoptotic neutrophils tion of a distinct global transcriptional profile phils, another granulocyte population that is (), which leads to monocytes- early after infection, compared with that of rapidly recruited to almost all sites of infection macrophages’ taking on a proresolution activity7. -elicited neutrophils at the 3 npg and injury , also have a role in protection has During infection with Staphylococcus aureus, same site. In particular, they have augmented been poorly explored. In this issue of Nature however, neutrophils can secrete factors that expression of genes associated with type 2 , Chen et al. describe a previously are able to differentiate macrophages toward immunity, including Retnla, Chi3l3 and Il13. unknown and unexpected role for neutrophils an alternatively activated (M2) state8; this sug- Furthermore, coculture experiments reveal that in ‘training’ macrophages to acquire a long- gests that there are multiple mechanisms by production of the IL-13 by neutrophils term protective function against helminth which neutrophils can influence their innate obtained from mice after primary infection with larvae as they transit through the lungs4. cell neighbors during infection. N. brasiliensis is critical for favoring the enhance- Neutrophil function during infection has Chen et al. demonstrate that during pri- ment of factors associated with the alternative been investigated most extensively in response mary infection with Nippostrongylus brasiliensis activation of lung macrophages and upregula- to bacteria; during such infection, they have (a rodent helminth with a lifecycle similar to tion of CD11b expression. Thus, in a manner been long thought of as terminally differentiated that of the human hookworm), neutrophils can analogous to M2 macrophages, neutrophils are cells with a direct protective role3. Protection ‘instruct’ lung macrophages to take on altered described in this setting as taking on an alter- is mediated by their phagocytic ability, functions that confers on them the ability to natively activated (‘N2’) phenotype. One reason rapidly kill larval stages of the parasite during a for the importance of these N2 neutrophils in John R. Grainger is with the Manchester secondary challenge4 (Fig. 1). This macrophage long-term ‘training’ may be their large numbers Collaborative Centre for Research ‘memory’ is still evident at 45 days after infec- and close proximity to monocytes-macrophages and Faculty of Life Sciences of The University of tion and around 30 days after clearance of the during larva-driven inflammation. Manchester, Manchester, UK. Richard K. Grencis is helminth. Enhanced killing is dependent on sig- Acquisition of N2 features by neutrophils with the Faculty of Life Sciences of The University of naling via the α-chain of the receptor for inter- has been described before during infection Manchester, Manchester, UK. leukin 4 (IL-4) and the production of arginase-1, with S. aureus8. Here, as in infection with e-mail: [email protected] or which have been described as protective during N. brasiliensis, neutrophils are able to induce [email protected] infection with various helminths2. In addition, M2 polarization of macrophages, although

902 volume 15 number 10 october 2014 nature immunology news and views

this was attributed to IL-10 and the Primary infection Secondary infection CCL2 (the chemotactic protein MCP-1). How neutrophils take on an N2 phe- notype rather than classically activated (N1) phenotype was not investigated during infec- tion with S. aureus8 and is not fully described during infection with N. brasiliensis in the current study4. It is likely that type 2 cyto­ kines produced early by innate lymphoid cells (such as ILC2 cells) or factors derived from N. brasiliensis -presenting cells mediate this switch. Alternatively, products secreted directly Lung from helminths can result in altered function of innate cells9. Further exploration will be M2 macrophage ↑ CD11b needed to establish how neutrophils enter into ↑ Arg1 this state and whether N2 neutrophils are a Time common feature of various infections. Macrophage Neutrophil Perhaps one of the most surprising observa- IL-13 tions by Chen et al. is that acquired immunity to the larval stage of the parasite trafficking through the does not require the adap- tive immune system4. It is intriguing that appropriate ‘training’ of the innate alone is entirely responsible for the protection observed in this model. Such ‘train- Gut ing’ of the can provide protection against Candida albicans in the absence of an adaptive immune response10, and lung macrophages can be maintained in an immunologically altered state following viral infection11. The longevity of specific Expulsion Expulsion populations of macrophages residing in the lungs may provide an explanation for the lack

of necessity for adaptive immune responses Group Publishing Caesar/Nature Kim to provide secondary protection at this site. Figure 1 Neutrophils ‘train’ lung macrophages to take on features that protect against helminth Although it is unclear from this study4 which larvae during secondary infection. In a primary infection (left), following entry through the skin, Nature America, Inc. All rights reserved. America, Inc. © 201 4 Nature population of macrophages is targeted by N. brasiliensis larvae are poorly impeded by the immune system and transit to the lungs, where neutrophils, the lung neutrophils are rapidly recruited. At this site, neutrophils take on an N2 phenotype that is associated with production of IL-13, as well as other factors, that ‘train’ macrophage function to support the killing of population represents a likely candidate. parasites (blue, before training; red, after acquisition of the M2 phenotype). However, larvae are not killed npg Alveolar macrophages are an extremely long- at this stage, and they transit to the gut, where during primary infection worms are completely expelled, lived population that can expand locally in large part by enhancement of goblet-cell secretion and gut peristalsis. The macrophages in the lungs after infection12. It is well established that remain in a ‘trained’ state for at least 45 days, until there is a subsequent invasion of N. brasiliensis, at epigenetic regulation is critical for the M2 polar- which time they kill the parasite in a manner dependent on CD11b and arginase-1 (Arg1). Although in ization of macrophages13. Therefore, long-term this setting much protection is mediated in the skin (in an antigen-specific manner), these reprogrammed epigenetic reprogramming of these cells may lung M2 macrophages provide a second level of protection that is independent of the . In contrast to primary infection, during secondary challenge (right) the gut is not a key mediator underlie their modified protective state. of protection, as small numbers of worms survive to reach this site. Vertical bars (right and left margins) Whereas the data in the present study indicate minor (yellow) or major (red) sites of protection. underscore the importance of ‘training’ lung macrophages in acquired immunity, other tis- are involved in mediating complete expulsion of immune system is that the macrophages in the sue sites are also critical in protecting against the parasite2. In a secondary infection, on the skin turn over much more rapidly than those in helminths. During infection with N. brasil- other hand, the skin has been described as a the lungs and thus long-term ‘training’ of skin iensis, the parasite first invades through major (if not complete) bulwark of immunity5. macrophages is not possible. Even in secondary the skin, then transits through the - At this tissue site, the adaptive immune system infection, any parasites that do survive transit stream to the lungs and ultimately travels is critical in providing antigen-specific protec- through both the skin and lungs are expelled by to the gut, where the adult worm produces tion, as basophils armed with immunoglobulin the gut (Fig. 1). eggs for transmission to new hosts (Fig. 1). E are required in favoring the M2 polarization of Overall, this study4 highlights the importance Following a primary infection, the majority of macrophages. Regardless of the setting, it appears of neutrophils beyond their well-described the protection against the helminth is mediated critical that macrophages take on the M2 phe- role as a pathogen-killing population during in the gut, in which secretions initiated by cells of notype and, in particular, produce arginase5. bacterial infection. Future research based on the immune system, especially goblet cells, and A hypothesis for the differences between the skin this study by Chen et al.4 will no doubt aim to peristalsis (so-called ‘weep and sweep’ responses) and lungs in their requirement for the adaptive elucidate whether the N2 differentiation and

nature immunology volume 15 number 10 octoberOctober 2014 903 news and views

function of neutrophils can be manipulated COMPETING FINANCIAL INTERESTS 7. Serhan, C.N. & Savill, J. Nat. Immunol. 6, 1191–1197 to support long-term protection against hel- The authors declare no competing financial interests. (2005). 8. Tsuda, Y. et al. Immunity 21, 215–226 (2004). minth infection. What remains to be explored 1. Africa, C.M. J. Parasitol. 18, 1–13 (1931). 9. Hewitson, J.P., Grainger, J.R. & Maizels, R.M. Mol. is whether the ‘training’ of macrophages by 2. Allen, J.E. & Maizels, R.M. Nat. Rev. Immunol. 11, Biochem. Parasitol. 167, 1–11 (2009). neutrophils is a common feature of lung inflam- 375–388 (2011). 10. Quintin, J. et al. Cell Host Microbe 12, 223–232 3. Amulic, B. et al. Annu. Rev. Immunol. 30, 459–489 (2012). mation and if targeting of this interaction could (2012). 11. Didierlaurent, A. et al. J. Exp. Med. 205, 323–329 provide a novel therapeutic avenue for some of 4. Chen F. et al. Nat. Immunol. 15, 938–946 (2014). (2008). 12. Hashimoto, D. 38, 792–804 the vast array of respiratory diseases afflicting 5. Obata-Ninomiya, K. et al. J. Exp. Med. 210, et al. Immunity 2583–2595 (2013). (2013). the world today, such as chronic obstructive 6. Pesce, J.T. et al. J. Immunol. 180, 464–474 13. Satoh, T. et al. Nat. Immunol. 11, 936–944 pulmonary disease or . (2008). (2010). Bcl-6 gets T cells off the sugar

Kevin Man & Axel Kallies The transcriptional regulator Bcl-6 represses aerobic glycolysis in CD8+ and CD4+ type 1 helper T cells.

uring the course of an adaptive immune in the tricarboxylic acid cycle. In contrast to antigen receptor, IRF4, is required for sustained Dresponse, metabolism is dynami- activated T cells, resting T cells use oxidative glycolysis in effector CD8+ T cells. Genetic abla- cally regulated and is subject to differentiation phosphorylation and fatty acid oxidation to tion of IRF4 results in profound impairment stage–specific regulation. In particular, antigen- fulfill their metabolic requirements and gener- in clonal expansion and loss of antigen-specific triggered activation of T cells is characterized by ate chemical energy in the form of ATP from effector T cells during viral or bacterial infection8. the transition from the catabolic state of naive the breakdown of pyruvate in the tricarboxylic Furthermore, IRF4 is required for the efficient or quiescent cells to the anabolic state of rapidly acid cycle. Although aerobic glycolysis, used by expression of HIF-1α, an oxygen-sensitive key proliferating effector cells1. During this process, activated cells, is a relatively inefficient process, transcriptional regulator of metabolic processes the cells ‘rewire’ their metabolic profile and switch it produces intermediary metabolites that fuel that mediates the transition from oxidative from oxidative phosphorylation and fatty acid anabolic biosynthetic pathways that support phosphorylation to aerobic glycolysis and allows oxidation to aerobic glycolysis. The transcrip- the rapid proliferation and function of effector metabolic adaptation to hypoxic microenviron- tion factors that mediate this metabolic transition T cells. This includes the synthesis of nucleotides, ments. HIF-1α can also be induced by signaling in T cells remain poorly defined. In this issue of amino acids and lipids needed to generate cel- via Toll-like receptors and activity of the meta- Nature Immunology, Weinmann and colleagues lular progeny3. Upon clearance of the antigen, bolic checkpoint kinase complex mTORC1 even reveal that the BTB–zinc-finger transcription fac- most effector T cells undergo , whereas under conditions of normal oxygen tension9. tor Bcl-6 is a critical regulator of the metabolic a proportion of memory precursor cells give Maintenance of HIF-1α expression in CD8+ changes that parallel the transition from effector rise to long-lived memory T cells. Although the T cells requires sustained IL-2 signaling, and it Nature America, Inc. All rights reserved. America, Inc. © 201 4 Nature T cell to memory T cell2. Specifically, Bcl-6 acts as metabolic profile of memory T cells is similar is partly through this mechanism that IL-2 pro- a repressor of genes encoding molecules involved to that of naive T cells, they are unique in that motes effector differentiation and glycolysis10. in aerobic glycolysis that are upregulated by high they have larger mitochondria and actively In their study, Weinmann and colleagues show

npg environmental concentrations of 2 transcribe genes encoding molecules involved that HIF-1α and Bcl-6 reciprocally regulate genes (IL-2) during the effector phase of the immune in mitochondrial biogenesis and the uptake of encoding molecules that control glucose metabo- response. Thus, this study offers important insight fatty acids, which is stimulated by the memory- lism in an IL-2-sensitive manner2. Using a vari- into how the formation of long-term memory promoting cytokine IL-15 (ref. 4). Therefore, during ety of in vitro approaches in CD4+ type 1 helper + cells is linked to the transcriptional regulation of memory formation, activated T cells revert back T cells (TH1 cells) and CD8 T cells cultured in distinct metabolic pathways. to catabolic metabolic pathways, reengaging in low and high concentrations of IL-2, the authors When naive T cells encounter foreign antigen oxidative phosphorylation and fatty acid oxida- confirm published results11, showing that genes in conjunction with other immunomodulatory tion for energy production5 (Fig. 1). encoding molecules involved in glucose metabo- signals, such as costimulation and IL-2, they Gene-regulatory networks that guide the lism are upregulated by high concentrations of undergo rapid clonal expansion and differenti- transition from mitochondrial oxidative phos- IL-2. These results correlate with increased occu- ate into effector or memory precursor T cells. phorylation to aerobic glycolysis are only begin- pancy of c-Myc and HIF-1α at the promoters of During this process, they reprogram their mito- ning to be elucidated, and even less is known genes encoding molecules involved in glycolysis. chondrial metabolism to aerobic glycolysis (the about the transcription factors that regulate Conversely, low concentrations of IL-2 favor Bcl-6 ‘Warburg effect’)3. In aerobic glycolysis, glucose- the reversion from aerobic glycolysis to oxida- expression and DNA-binding activity, which allows derived pyruvate in the cytosol is converted to tive phosphorylation and fatty acid oxidation Bcl-6-dependent repression of the same genes. The lactate, and small amounts of pyruvate enter the during memory development. T cell activation authors further demonstrate that the T-box tran- mitochondria to be oxidized to carbon dioxide induces early transcriptional regulators, includ- scription factor T-bet, which is critical for the dif- 6 7 + ing c-Myc and ERRα , that are important ferentiation of TH1 cells and CD8 effector T cells, Kevin Man and Axel Kallies are with the Molecular for inducing the expression of genes encod- is also required for the IL-2-dependent increase in Immunology Division at the Walter and Eliza Hall ing molecules involved in glycolysis and other the expression of genes encoding glycolysis-related Institute of Medical Research, Parkville, Australia. intermediary metabolic pathways. Another molecules2. T-bet antagonizes Bcl-6-dependent e-mail: [email protected]. transcription factor dependent on the T cell repression by interacting with Bcl-6 and masking its

904 volume 15 number 10 octoberOctober 2014 nature immunology