Editorial: New tricks for innate lymphoid cells By Gregory F. Sonnenberg1 Division of Gastroenterology, Department of Medicine, and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA RECEIVED JULY 10, 2013; REVISED AUGUST 12, 2013; ACCEPTED AUGUST 20, 2013. DOI: 10.1189/jlb.0713380
‹ SEE CORRESPONDING ARTICLE ON PAGE 877
I
LCs are an emerging family of innate immune cells that exhibit phenotypic and functional heterogeneity that is remarkably similar to effector subsets of CD4⫹ Th cells [1, 2]. As such, ILCs can be placed into three groups based on expression of cytokines, cytokine receptors, and transcription factors, including T-bet⫹ Group 1 ILCs that are comparable with Th1 cells, GATA3⫹ Group 2 ILCs that are comparable with Th2 cells, and retinoic acid receptor-related orphan receptor ␥t⫹ Group 3 ILCs that are comparable with Th17 cells and Th22 cells [1, 2]. Early studies investigating the functional potential of ILCs have identified that similar to CD4⫹ T cell effector subsets, ILCs can orchestrate context-dependent immunity or tissue inflammation via production of canonical effector cytokines. For example, Group 3 ILCs can promote IL-17- or IL-22-dependent antibacterial immunity and intestinal inflammation, whereas Group 2 ILCs can promote IL-5- or IL-13-dependent antiparasite immunity and allergic inflammation [3–7]. However, whether ILC subsets also have novel functions that extend beyond rapid expression of classical CD4⫹T cell-associated effector cytokines remains poorly understood. In this issue of the Journal of Leukocyte Biology, Locksley and colleagues [8] identify that in addition to Th2 cell-associated cytokines IL-5 and IL-13, Group 2 ILCs express the enzyme arginase-1 in the lungs of mice. Arginase-1 is a manganese metalloenzyme that catalyzes the conversion of the amino acid L-arginine
Abbreviations: AAMac⫽alternatively activated macrophage, ILC⫽innate lymphoid cell, RELM␣⫽resistin-like molecule ␣, Ym-1⫽chitinase3-like protein 3
862 Journal of Leukocyte Biology
into L-ornithine and urea [9, 10]. This enzymatic reaction is the final step of the urea cycle that is essential for hepatocyte conversion of harmful ammonia into urea prior to excretion from the host. Expression of arginase-1 in the liver is essential to maintain mammalian homeostasis, and mice genetically lacking Arg1 develop symptoms of hyperammonemia and die soon after birth [9, 10]. In addition to hepatocytes, arginase-1 is expressed within the mammalian immune system in response to parasites or allergens. Whereas not expressed in T cell populations, arginase-1 is expressed in myeloid cells during type 2 immunity or inflammation and is a hallmark of AAMacs along with other classical AAMac-associated genes, Ym-1 and RELM␣ [10, 11]. Intriguingly, Locksley and colleagues [8] identify that unlike AAMac expression of arginase-1, which is induced by IL-4- or IL-13-mediated activation of STAT6 [9, 10], ILC-intrinsic expression of arginase-1 occurs independently of STAT6, suggesting a novel pathway for induction. Consistent with this, Group 2 ILCs were found to constitutively express arginase-1 in multiple tissues derived from naive mice, including the lung, spleen, mesenteric LN, and small intestine. The cellular and molecular signals regulating constitutive ILC-intrinsic arginase-1 expression remain elusive; however, it was identified that IL-33–IL33R interactions in vivo could expand STAT6-independent arginase-1⫹ ILCs and STAT6-dependent arginase-1⫹ AAMacs. These data suggest that IL-33 can orchestrate arginase-1 responses indirectly by promoting expansion of arginase-1⫹ Group 2 ILCs and mediating AAMac differentiation via STAT6 signaling from ILC-derived IL-13- or IL-5-mediated recruitment of IL-4⫹ eosinophils Volume 94, November 2013
(Fig. 1). Further studies will be necessary to define the STAT6-independent pathways responsible for ILC-intrinsic expression of arginase-1 in the steady state and following infection or inflammation. Some potential insight may be drawn from studies identifying a novel pathway of arginase-1 expression in macrophages following Mycobacterium tuberculosis infection, which involves TLR/MyD88 stimulation and STAT3dependent signals [12, 13]. Intriguingly, this STAT3-regulated pathway did not induce coexpression of other classical AAMac-associated genes, which is more similar to the low or absent coexpression of Ym-1 and RELM␣ in arginase-1⫹ Group 2 ILCs described by Locksley and colleagues [8]. AAMac-intrinsic arginase-1 expression has been proposed to be a critical regulator of immunity and tissue fibrosis in response to parasitic infection or allergic inflammation [9, 10]. These properties are a function of L-arginine metabolism by arginase-1⫹ AAMacs. For example, AAMac-derived arginase-1 can counter-regulate other enzymes requiring the L-arginine substrate, including NOS that catalyzes production of ROS and play a critical role in immunity to bacteria and tumors. Furthermore, a byproduct of L-arginine metabolism is L-ornithine, which can be processed further to L-proline, a critical amino acid for collagen synthesis and fibrotic responses. In contrast to these proposed functions for AAMac-intrinsic arginse-1, Locksley and colleagues [8] demonstrate that genetic deletion of arginase-1
1. Correspondence: Division of Gastroenterology, Dept. of Medicine, and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. E-mail: [email protected]
www.jleukbio.org
EDITORIAL Sonnenberg New tricks for innate lymphoid cells
Allergen or parasite challenge
IL-33 Group 2 ILC
AAMac
Ym-1
II5 II13
RELMα
IL-13
? Arg1
L-Arginine
STAT6independent
STAT6
Arg1
IL-5
Arg1 L-Ornithine urea
? IL-4 T cell regulation? Tissue repair? Fibrosis? Parasite immunity?
Proline/collagen NOS activity/ROS production T cell responses
Eosinophil Figure 1. Arginase-1 expression in Group 2 ILCs and AAMacs. At barrier surfaces of the body, allergen or infectious challenges induce IL-33 from epithelial cells, which promotes expansion of ILCs and promotes AAMac differentiation indirectly through STAT6-dependent signals. AAMac-intrinsic arginase-1 expression is induced by IL-4 and IL-13 in a STAT6-dependent manner and has been proposed to augment collagen production, NOS activity, and T cell responses. Conversely, Locksley and colleagues [8] identify that arginase-1 is constitutively expressed in Group 2 ILCs in a STAT6-independent manner. However, the regulation and functional potential of ILC-intrinsic arginase-1 remain undetermined.
in ILCs did not impair ILC expansion, cytokine production, and collagen disposition in the lung or worm clearance from the gastrointestinal tract following Nippostrongylus brasiliensis infection. Therefore, the function of ILC-intrinsic arginase-1 in homeostasis, tissue inflammation, and immunity remains undefined and will be an important area of future investigation (Fig. 1). As it has been identified that myeloid-derived arginase-1 only regulates allergic inflammation in selective contexts [14], it is www.jleukbio.org
likely that multiple models of allergen of infectious challenge will need to be used to fully appreciate the functional potential of arginase-1 expression in Group 2 ILCs. Other studies have suggested that arginase-1 expression in AAMacs can play a critical regulatory role by limiting the magnitude of T cell responses in the context of tumors or parasitic infection [12, 15]. This was proposed to occur by reducing the bioavailability of L-arginine to T cells, which can limit T cell exVolume 94, November 2013
pansion and cytokine production [16]. Therefore, it remains possible that Group 2 ILC expression of arginase-1 may play a critical role in regulating T cell responses in the steady-state or following infectious or inflammatory challenge. Although not yet tested, this would parallel a recently identified role for Group 3 ILCs in restraining pathologic Th17 cell responses in the intestine via MHCII [17]. Therefore, one could hypothesize that in addition to providing an early innate source of efJournal of Leukocyte Biology 863
fector cytokines, elicited ILC populations may play a critical role in restraining the magnitude of corresponding effector CD4⫹ T cell responses and preventing immunopathology through novel cytokine-independent pathways. Finally, arginase-1 expression in Group 2 ILCs may yield novel functions for arginase-1 that are not yet determined. Recent studies have identified that Group 2 ILCs are enriched at barrier surfaces of the body and play a critical role in tissue repair through expression of growth factors, such as amphiregulin [18]. Therefore ILC-intrinsic expression of arginase-1 may influence the ability of Group 2 ILCs to promote maintenance or restoration of epithelial barriers following damage or may exhibit novel synergistic or inhibitory functions with other cytokines coexpressed by ILCs, such as IL-5 and IL-13. Whereas several fundamental questions regarding the regulation and functional potential of Group 2 ILC-intrinsic arginase-1 remain unanswered, the report by Locksley and colleagues [8] supports an emerging hypothesis that ILCs may play critical roles in orchestrating immune responses through mechanisms that are independent of rapid cytokine production. Importantly, this report also identifies arginase-1 as a novel marker that can be used to distinguish Group 2 ILCs from CD4⫹ Th2 cells. This adds another layer of complexity to the functional potential of ILCs and may provoke new insight into the role of ILC subsets in health and disease.
tious Diseases (NIAID) Mucosal Immunology Studies Team (MIST) Scholar Award in Mucosal Immunity, and the Molecular Studies in Digestive and Liver Disease Molecular Pathology and Imaging Core (P30DK50306). REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
ACKNOWLEDGMENTS Research in the Sonnenberg laboratory is supported by the U.S. National Institutes of Health (DP5OD012116), the National Institute of Allergy and Infec-
864 Journal of Leukocyte Biology
12.
10.
11.
Spits, H., Artis, D., Colonna, M., Diefenbach, A., Di Santo, J. P., Eberl, G., Koyasu, S., Locksley, R. M., McKenzie, A. N., Mebius, R. E., Powrie, F., Vivier, E. (2013) Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149. Sonnenberg, G. F., Artis, D. (2012) Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37, 601–610. Buonocore, S., Ahern, P. P., Uhlig, H. H., Ivanov, I. I., Littman, D. R., Maloy, K. J., Powrie, F. (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375. Chang, Y. J., Kim, H. Y., Albacker, L. A., Baumgarth, N., McKenzie, A. N., Smith, D. E., Dekruyff, R. H., Umetsu, D. T. (2011) Innate lymphoid cells mediate influenzainduced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631–638. Neill, D. R., Wong, S. H., Bellosi, A., Flynn, R. J., Daly, M., Langford, T. K., Bucks, C., Kane, C. M., Fallon, P. G., Pannell, R., Jolin, H. E., McKenzie, A. N. (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367– 1370. Sonnenberg, G. F., Monticelli, L. A., Elloso, M. M., Fouser, L. A., Artis, D. (2011) CD4(⫹) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122–134. Cella, M., Fuchs, A., Vermi, W., Facchetti, F., Otero, K., Lennerz, J. K., Doherty, J. M., Mills, J. C., Colonna, M. (2009) A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725. Bando, J. K., Nussbaum, J. C., Liang, H. E., Locksley, R. M. (2013) Type 2 innate lymphoid cells constitutively express arginase-I in the naive and inflamed lung. J. Leukoc. Biol. 94, . Bronte, V., Zanovello, P. (2005) Regulation of immune responses by L-arginine metabolism. Nat. Rev. Immunol. 5, 641–654. Van Dyken, S. J., Locksley, R. M. (2013) Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu. Rev. Immunol. 31, 317–343. Nair, M. G., Cochrane, D. W., Allen, J. E. (2003) Macrophages in chronic type 2 in-
Volume 94, November 2013
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flammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Immunol. Lett. 85, 173–180. El Kasmi, K. C., Qualls, J. E., Pesce, J. T., Smith, A. M., Thompson, R. W., HenaoTamayo, M., Basaraba, R. J., Konig, T., Schleicher, U., Koo, M. S., Kaplan, G., Fitzgerald, K. A., Tuomanen, E. I., Orme, I. M., Kanneganti, T. D., Bogdan, C., Wynn, T. A., Murray, P. J. (2008) Toll-like receptorinduced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat. Immunol. 9, 1399 –1406. Qualls, J. E., Neale, G., Smith, A. M., Koo, M. S., DeFreitas, A. A., Zhang, H., Kaplan, G., Watowich, S. S., Murray, P. J. (2010) Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling. Sci. Signal. 3, ra62. Barron, L., Smith, A. M., El Kasmi, K. C., Qualls, J. E., Huang, X., Cheever, A., Borthwick, L. A., Wilson, M. S., Murray, P. J., Wynn, T. A. (2013) Role of arginase 1 from myeloid cells in th2-dominated lung inflammation. PLoS One 8, e61961. Rodriguez, P. C., Quiceno, D. G., Zabaleta, J., Ortiz, B., Zea, A. H., Piazuelo, M. B., Delgado, A., Correa, P., Brayer, J., Sotomayor, E. M., Antonia, S., Ochoa, J. B., Ochoa, A. C. (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 64, 5839 –5849. Pesce, J. T., Ramalingam, T. R., MentinkKane, M. M., Wilson, M. S., El Kasmi, K. C., Smith, A. M., Thompson, R. W., Cheever, A. W., Murray, P. J., Wynn, T. A. (2009) Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog. 5, e1000371. Hepworth, M. R., Monticelli, L. A., Fung, T. C., Ziegler, C. G., Grunberg, S., Sinha, R., Mantegazza, A. R., Ma, H. L., Crawford, A., Angelosanto, J. M., Wherry, E. J., Koni, P. A., Bushman, F. D., Elson, C. O., Eberl, G., Artis, D., Sonnenberg, G. F. (2013) Innate lymphoid cells regulate CD4⫹ T-cell responses to intestinal commensal bacteria. Nature 498, 113–117. Monticelli, L. A., Sonnenberg, G. F., Abt, M. C., Alenghat, T., Ziegler, C. G., Doering, T. A., Angelosanto, J. M., Laidlaw, B. J., Yang, C. Y., Sathaliyawala, T., Kubota, M., Turner, D., Diamond, J. M., Goldrath, A. W., Farber, D. L., Collman, R. G., Wherry, E. J., Artis, D. (2011) Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054.
KEY WORDS: Arginase-1 䡠 allergic inflammation 䡠 innate immunity
www.jleukbio.org
‹ SEE CORRESPONDING ARTICLE ON PAGE 877
I
LCs are an emerging family of innate immune cells that exhibit phenotypic and functional heterogeneity that is remarkably similar to effector subsets of CD4⫹ Th cells [1, 2]. As such, ILCs can be placed into three groups based on expression of cytokines, cytokine receptors, and transcription factors, including T-bet⫹ Group 1 ILCs that are comparable with Th1 cells, GATA3⫹ Group 2 ILCs that are comparable with Th2 cells, and retinoic acid receptor-related orphan receptor ␥t⫹ Group 3 ILCs that are comparable with Th17 cells and Th22 cells [1, 2]. Early studies investigating the functional potential of ILCs have identified that similar to CD4⫹ T cell effector subsets, ILCs can orchestrate context-dependent immunity or tissue inflammation via production of canonical effector cytokines. For example, Group 3 ILCs can promote IL-17- or IL-22-dependent antibacterial immunity and intestinal inflammation, whereas Group 2 ILCs can promote IL-5- or IL-13-dependent antiparasite immunity and allergic inflammation [3–7]. However, whether ILC subsets also have novel functions that extend beyond rapid expression of classical CD4⫹T cell-associated effector cytokines remains poorly understood. In this issue of the Journal of Leukocyte Biology, Locksley and colleagues [8] identify that in addition to Th2 cell-associated cytokines IL-5 and IL-13, Group 2 ILCs express the enzyme arginase-1 in the lungs of mice. Arginase-1 is a manganese metalloenzyme that catalyzes the conversion of the amino acid L-arginine
Abbreviations: AAMac⫽alternatively activated macrophage, ILC⫽innate lymphoid cell, RELM␣⫽resistin-like molecule ␣, Ym-1⫽chitinase3-like protein 3
862 Journal of Leukocyte Biology
into L-ornithine and urea [9, 10]. This enzymatic reaction is the final step of the urea cycle that is essential for hepatocyte conversion of harmful ammonia into urea prior to excretion from the host. Expression of arginase-1 in the liver is essential to maintain mammalian homeostasis, and mice genetically lacking Arg1 develop symptoms of hyperammonemia and die soon after birth [9, 10]. In addition to hepatocytes, arginase-1 is expressed within the mammalian immune system in response to parasites or allergens. Whereas not expressed in T cell populations, arginase-1 is expressed in myeloid cells during type 2 immunity or inflammation and is a hallmark of AAMacs along with other classical AAMac-associated genes, Ym-1 and RELM␣ [10, 11]. Intriguingly, Locksley and colleagues [8] identify that unlike AAMac expression of arginase-1, which is induced by IL-4- or IL-13-mediated activation of STAT6 [9, 10], ILC-intrinsic expression of arginase-1 occurs independently of STAT6, suggesting a novel pathway for induction. Consistent with this, Group 2 ILCs were found to constitutively express arginase-1 in multiple tissues derived from naive mice, including the lung, spleen, mesenteric LN, and small intestine. The cellular and molecular signals regulating constitutive ILC-intrinsic arginase-1 expression remain elusive; however, it was identified that IL-33–IL33R interactions in vivo could expand STAT6-independent arginase-1⫹ ILCs and STAT6-dependent arginase-1⫹ AAMacs. These data suggest that IL-33 can orchestrate arginase-1 responses indirectly by promoting expansion of arginase-1⫹ Group 2 ILCs and mediating AAMac differentiation via STAT6 signaling from ILC-derived IL-13- or IL-5-mediated recruitment of IL-4⫹ eosinophils Volume 94, November 2013
(Fig. 1). Further studies will be necessary to define the STAT6-independent pathways responsible for ILC-intrinsic expression of arginase-1 in the steady state and following infection or inflammation. Some potential insight may be drawn from studies identifying a novel pathway of arginase-1 expression in macrophages following Mycobacterium tuberculosis infection, which involves TLR/MyD88 stimulation and STAT3dependent signals [12, 13]. Intriguingly, this STAT3-regulated pathway did not induce coexpression of other classical AAMac-associated genes, which is more similar to the low or absent coexpression of Ym-1 and RELM␣ in arginase-1⫹ Group 2 ILCs described by Locksley and colleagues [8]. AAMac-intrinsic arginase-1 expression has been proposed to be a critical regulator of immunity and tissue fibrosis in response to parasitic infection or allergic inflammation [9, 10]. These properties are a function of L-arginine metabolism by arginase-1⫹ AAMacs. For example, AAMac-derived arginase-1 can counter-regulate other enzymes requiring the L-arginine substrate, including NOS that catalyzes production of ROS and play a critical role in immunity to bacteria and tumors. Furthermore, a byproduct of L-arginine metabolism is L-ornithine, which can be processed further to L-proline, a critical amino acid for collagen synthesis and fibrotic responses. In contrast to these proposed functions for AAMac-intrinsic arginse-1, Locksley and colleagues [8] demonstrate that genetic deletion of arginase-1
1. Correspondence: Division of Gastroenterology, Dept. of Medicine, and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. E-mail: [email protected]
www.jleukbio.org
EDITORIAL Sonnenberg New tricks for innate lymphoid cells
Allergen or parasite challenge
IL-33 Group 2 ILC
AAMac
Ym-1
II5 II13
RELMα
IL-13
? Arg1
L-Arginine
STAT6independent
STAT6
Arg1
IL-5
Arg1 L-Ornithine urea
? IL-4 T cell regulation? Tissue repair? Fibrosis? Parasite immunity?
Proline/collagen NOS activity/ROS production T cell responses
Eosinophil Figure 1. Arginase-1 expression in Group 2 ILCs and AAMacs. At barrier surfaces of the body, allergen or infectious challenges induce IL-33 from epithelial cells, which promotes expansion of ILCs and promotes AAMac differentiation indirectly through STAT6-dependent signals. AAMac-intrinsic arginase-1 expression is induced by IL-4 and IL-13 in a STAT6-dependent manner and has been proposed to augment collagen production, NOS activity, and T cell responses. Conversely, Locksley and colleagues [8] identify that arginase-1 is constitutively expressed in Group 2 ILCs in a STAT6-independent manner. However, the regulation and functional potential of ILC-intrinsic arginase-1 remain undetermined.
in ILCs did not impair ILC expansion, cytokine production, and collagen disposition in the lung or worm clearance from the gastrointestinal tract following Nippostrongylus brasiliensis infection. Therefore, the function of ILC-intrinsic arginase-1 in homeostasis, tissue inflammation, and immunity remains undefined and will be an important area of future investigation (Fig. 1). As it has been identified that myeloid-derived arginase-1 only regulates allergic inflammation in selective contexts [14], it is www.jleukbio.org
likely that multiple models of allergen of infectious challenge will need to be used to fully appreciate the functional potential of arginase-1 expression in Group 2 ILCs. Other studies have suggested that arginase-1 expression in AAMacs can play a critical regulatory role by limiting the magnitude of T cell responses in the context of tumors or parasitic infection [12, 15]. This was proposed to occur by reducing the bioavailability of L-arginine to T cells, which can limit T cell exVolume 94, November 2013
pansion and cytokine production [16]. Therefore, it remains possible that Group 2 ILC expression of arginase-1 may play a critical role in regulating T cell responses in the steady-state or following infectious or inflammatory challenge. Although not yet tested, this would parallel a recently identified role for Group 3 ILCs in restraining pathologic Th17 cell responses in the intestine via MHCII [17]. Therefore, one could hypothesize that in addition to providing an early innate source of efJournal of Leukocyte Biology 863
fector cytokines, elicited ILC populations may play a critical role in restraining the magnitude of corresponding effector CD4⫹ T cell responses and preventing immunopathology through novel cytokine-independent pathways. Finally, arginase-1 expression in Group 2 ILCs may yield novel functions for arginase-1 that are not yet determined. Recent studies have identified that Group 2 ILCs are enriched at barrier surfaces of the body and play a critical role in tissue repair through expression of growth factors, such as amphiregulin [18]. Therefore ILC-intrinsic expression of arginase-1 may influence the ability of Group 2 ILCs to promote maintenance or restoration of epithelial barriers following damage or may exhibit novel synergistic or inhibitory functions with other cytokines coexpressed by ILCs, such as IL-5 and IL-13. Whereas several fundamental questions regarding the regulation and functional potential of Group 2 ILC-intrinsic arginase-1 remain unanswered, the report by Locksley and colleagues [8] supports an emerging hypothesis that ILCs may play critical roles in orchestrating immune responses through mechanisms that are independent of rapid cytokine production. Importantly, this report also identifies arginase-1 as a novel marker that can be used to distinguish Group 2 ILCs from CD4⫹ Th2 cells. This adds another layer of complexity to the functional potential of ILCs and may provoke new insight into the role of ILC subsets in health and disease.
tious Diseases (NIAID) Mucosal Immunology Studies Team (MIST) Scholar Award in Mucosal Immunity, and the Molecular Studies in Digestive and Liver Disease Molecular Pathology and Imaging Core (P30DK50306). REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
ACKNOWLEDGMENTS Research in the Sonnenberg laboratory is supported by the U.S. National Institutes of Health (DP5OD012116), the National Institute of Allergy and Infec-
864 Journal of Leukocyte Biology
12.
10.
11.
Spits, H., Artis, D., Colonna, M., Diefenbach, A., Di Santo, J. P., Eberl, G., Koyasu, S., Locksley, R. M., McKenzie, A. N., Mebius, R. E., Powrie, F., Vivier, E. (2013) Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149. Sonnenberg, G. F., Artis, D. (2012) Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37, 601–610. Buonocore, S., Ahern, P. P., Uhlig, H. H., Ivanov, I. I., Littman, D. R., Maloy, K. J., Powrie, F. (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375. Chang, Y. J., Kim, H. Y., Albacker, L. A., Baumgarth, N., McKenzie, A. N., Smith, D. E., Dekruyff, R. H., Umetsu, D. T. (2011) Innate lymphoid cells mediate influenzainduced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631–638. Neill, D. R., Wong, S. H., Bellosi, A., Flynn, R. J., Daly, M., Langford, T. K., Bucks, C., Kane, C. M., Fallon, P. G., Pannell, R., Jolin, H. E., McKenzie, A. N. (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367– 1370. Sonnenberg, G. F., Monticelli, L. A., Elloso, M. M., Fouser, L. A., Artis, D. (2011) CD4(⫹) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122–134. Cella, M., Fuchs, A., Vermi, W., Facchetti, F., Otero, K., Lennerz, J. K., Doherty, J. M., Mills, J. C., Colonna, M. (2009) A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725. Bando, J. K., Nussbaum, J. C., Liang, H. E., Locksley, R. M. (2013) Type 2 innate lymphoid cells constitutively express arginase-I in the naive and inflamed lung. J. Leukoc. Biol. 94, . Bronte, V., Zanovello, P. (2005) Regulation of immune responses by L-arginine metabolism. Nat. Rev. Immunol. 5, 641–654. Van Dyken, S. J., Locksley, R. M. (2013) Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu. Rev. Immunol. 31, 317–343. Nair, M. G., Cochrane, D. W., Allen, J. E. (2003) Macrophages in chronic type 2 in-
Volume 94, November 2013
13.
14.
15.
16.
17.
18.
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KEY WORDS: Arginase-1 䡠 allergic inflammation 䡠 innate immunity
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