Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence

Abstract

Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers1. ILC3 development is thought to be programmed1, but how ILC3 perceive, integrate and respond to local environmental signals remains unclear. Here we show that ILC3 in mice sense their environment and control gut defence as part of a glial–ILC3–epithelial cell unit orchestrated by neurotrophic factors. We found that enteric ILC3 express the neuroregulatory receptor RET. ILC3-autonomous Ret ablation led to decreased innate interleukin-22 (IL-22), impaired epithelial reactivity, dysbiosis and increased susceptibility to bowel inflammation and infection. Neurotrophic factors directly controlled innate Il22 downstream of the p38 MAPK/ERK-AKT cascade and STAT3 activation. Notably, ILC3 were adjacent to neurotrophic-factor-expressing glial cells that exhibited stellate-shaped projections into ILC3 aggregates. Glial cells sensed microenvironmental cues in a MYD88-dependent manner to control neurotrophic factors and innate IL-22. Accordingly, glial-intrinsic Myd88 deletion led to impaired production of ILC3-derived IL-22 and a pronounced propensity towards gut inflammation and infection. Our work sheds light on a novel multi-tissue defence unit, revealing that glial cells are central hubs of neuron and innate immune regulation by neurotrophic factor signals.

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Figure 1: The neurotrophic factor receptor RET drives enteric ILC3-derived IL-22.
Figure 2: ILC3-intrinsic RET signals regulate gut defence.
Figure 3: ILC3-autonomous RET signals directly control Il22 downstream of pSTAT3.
Figure 4: Glial cells set GFL expression and innate IL-22 via MYD88-dependent sensing of the microenvironment.

References

  1. 1

    Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015)

  2. 2

    van de Pavert, S. A. et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014)

  3. 3

    Spencer, S. P. et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014)

  4. 4

    Kiss, E. A. et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011)

  5. 5

    Lee, J. S. et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 13, 144–151 (2011)

  6. 6

    Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012)

  7. 7

    Mulligan, L. M. RET revisited: expanding the oncogenic portfolio. Nat. Rev. Cancer 14, 173–186 (2014)

  8. 8

    Fonseca-Pereira, D. et al. The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function. Nature 514, 98–101 (2014)

  9. 9

    Veiga-Fernandes, H. et al. Tyrosine kinase receptor RET is a key regulator of Peyer’s patch organogenesis. Nature 446, 547–551 (2007)

  10. 10

    Patel, A. et al. Differential RET signaling pathways drive development of the enteric lymphoid and nervous systems. Sci. Signal. 5, ra55 (2012)

  11. 11

    Almeida, A. R. et al. The neurotrophic factor receptor RET regulates IL-10 production by in vitro polarised T helper 2 cells. Eur. J. Immunol. 44, 3605–3613 (2014)

  12. 12

    Robinette, M. L. et al. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat. Immunol. 16, 306–317 (2015)

  13. 13

    Hoshi, M., Batourina, E., Mendelsohn, C. & Jain, S. Novel mechanisms of early upper and lower urinary tract patterning regulated by RetY1015 docking tyrosine in mice. Development 139, 2405–2415 (2012)

  14. 14

    Smith-Hicks, C. L., Sizer, K. C., Powers, J. F., Tischler, A. S. & Costantini, F. C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B. EMBO J. 19, 612–622 (2000)

  15. 15

    Sawa, S. et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010)

  16. 16

    Almeida, A. R. et al. RET/GFRα signals are dispensable for thymic T cell development in vivo. PLoS One 7, e52949 (2012)

  17. 17

    Rutz, S., Wang, X. & Ouyang, W. The IL-20 subfamily of cytokines--from host defence to tissue homeostasis. Nat. Rev. Immunol. 14, 783–795 (2014)

  18. 18

    Xu, W. et al. NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Cell Reports 10, 2043–2054 (2015)

  19. 19

    Wen, H. et al. ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression. Nature 508, 263–268 (2014)

  20. 20

    Garrett, W. S. et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8, 292–300 (2010)

  21. 21

    Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011)

  22. 22

    Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004)

  23. 23

    Neunlist, M. et al. The digestive neuronal-glial-epithelial unit: a new actor in gut health and disease. Nat. Rev. Gastroenterol. Hepatol. 10, 90–100 (2013)

  24. 24

    Brun, P. et al. Toll-like receptor 2 regulates intestinal inflammation by controlling integrity of the enteric nervous system. Gastroenterology 145, 1323–1333 (2013)

  25. 25

    Kabouridis, P. S. et al. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron 85, 289–295 (2015)

  26. 26

    Zhuo, L. et al. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 31, 85–94 (2001)

  27. 27

    Hou, B., Reizis, B. & DeFranco, A. L. Toll-like receptors activate innate and adaptive immunity by using dendritic cell-intrinsic and -extrinsic mechanisms. Immunity 29, 272–282 (2008)

  28. 28

    van de Pavert, S. A. et al. Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat. Immunol. 10, 1193–1199 (2009)

  29. 29

    Bush, T. G. et al. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 93, 189–201 (1998)

  30. 30

    Veiga-Fernandes, H. & Mucida, D. Neuro-Immune Interactions at Barrier Surfaces. Cell 165, 801–811 (2016)

  31. 31

    Cao, X. et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity 2, 223–238 (1995)

  32. 32

    Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992)

  33. 33

    Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001)

  34. 34

    Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010)

  35. 35

    Horai, R. et al. Production of mice deficient in genes for interleukin (IL)-1α, IL-1β, IL-1α/β, and IL-1 receptor antagonist shows that IL-1β is crucial in turpentine-induced fever development and glucocorticoid secretion. J. Exp. Med. 187, 1463–1475 (1998)

  36. 36

    Adachi, O. et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143–150 (1998)

  37. 37

    Wiles, S., Pickard, K. M., Peng, K., MacDonald, T. T. & Frankel, G. In vivo bioluminescence imaging of the murine pathogen Citrobacter rodentium. Infect. Immun. 74, 5391–5396 (2006)

  38. 38

    Collins, J. W. et al. Citrobacter rodentium: infection, inflammation and the microbiota. Nat. Rev. Microbiol. 12, 612–623 (2014)

  39. 39

    Ibiza, S. et al. Endothelial nitric oxide synthase regulates T cell receptor signaling at the immunological synapse. Immunity 24, 753–765 (2006)

  40. 40

    Moolenbeek, C. & Ruitenberg, E. J. The “Swiss roll”: a simple technique for histological studies of the rodent intestine. Lab. Anim. 15, 57–59 (1981)

  41. 41

    Burich, A. et al. Helicobacter-induced inflammatory bowel disease in IL-10- and T cell-deficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G764–G778 (2001)

  42. 42

    Fort, M. M. et al. A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. J. Immunol. 174, 6416–6423 (2005)

  43. 43

    Seamons, A., Treuting, P. M., Brabb, T. & Maggio-Price, L. Characterization of dextran sodium sulfate-induced inflammation and colonic tumorigenesis in Smad3−/− mice with dysregulated TGFβ. PLoS One 8, e79182 (2013)

  44. 44

    Bogunovic, M. et al. Origin of the lamina propria dendritic cell network. Immunity 31, 513–525 (2009)

  45. 45

    Muller, P. A. et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014)

  46. 46

    Sanos, S. L. & Diefenbach, A. Isolation of NK cells and NK-like cells from the intestinal lamina propria. Methods Mol. Biol. 612, 505–517 (2010)

  47. 47

    Joseph, N. M. et al. Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut. J. Clin. Invest. 121, 3398–3411 (2011)

  48. 48

    Escobar, T. M. et al. miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve polycomb-mediated repression. Immunity 40, 865–879 (2014)

  49. 49

    Guo, X. et al. Induction of innate lymphoid cell-derived interleukin-22 by the transcription factor STAT3 mediates protection against intestinal infection. Immunity 40, 25–39 (2014)

  50. 50

    Yeste, A. et al. IL-21 induces IL-22 production in CD4+ T cells. Nat. Commun. 5, 3753 (2014)

  51. 51

    Misic, A. M. et al. The shared microbiota of humans and companion animals as evaluated from Staphylococcus carriage sites. Microbiome 3, 2 (2015)

  52. 52

    Schloss, P. D. et al. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl. Environ. Microbiol. 75, 7537–7541 (2009)

  53. 53

    Caporaso, J. G. et al. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335–336 (2010)

  54. 54

    Haas, B. J. et al. Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons. Genome Res. 21, 494–504 (2011)

  55. 55

    Fu, L., Niu, B., Zhu, Z., Wu, S. & Li, W. CD-HIT: accelerated for clustering the next-generation sequencing data. Bioinformatics 28, 3150–3152 (2012)

  56. 56

    Wang, Q., Garrity, G. M., Tiedje, J. M. & Cole, J. R. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl. Environ. Microbiol. 73, 5261–5267 (2007)

  57. 57

    Caporaso, J. G. et al. PyNAST: a flexible tool for aligning sequences to a template alignment. Bioinformatics 26, 266–267 (2010)

  58. 58

    Price, M. N., Dehal, P. S. & Arkin, A. P. FastTree: computing large minimum evolution trees with profiles instead of a distance matrix. Mol. Biol. Evol. 26, 1641–1650 (2009)

  59. 59

    Lozupone, C., Hamady, M. & Knight, R. UniFrac—an online tool for comparing microbial community diversity in a phylogenetic context. BMC Bioinformatics 7, 371 (2006)

  60. 60

    Mich, J. K. et al. Prospective identification of functionally distinct stem cells and neurosphere-initiating cells in adult mouse forebrain. eLife 3, e02669 (2014)

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Acknowledgements

We thank the Histology, Flow Cytometry, Bioimaging and Vivarium services at IMM; Sanjay Jain for providing RetGFP mice. Genentech for providing anti-IL-22 antibody. S.I. was supported by MEC, Spain and FCT, Portugal. B.G.-C. by FP7 (289720), EU. H.V.-F. by EMBO (1648); ERC (647274), EU; Kenneth Rainin Foundation, US; Crohn’s and Colitis Foundation of America, US; and FCT, Portugal. G.E. by Institut Pasteur and ANR, France. E.A.G. by NIH NIAMS R01 AR060873. A.M.M. by NIH NIAMS T32 AR007465 and Morris Animal Foundation (D14CA-404).

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S.I. and B.G.-C. designed, performed and analysed the experiments in Figs 1, 2, 3, 4 and Extended Data Figs 1–9. T.C. analysed the experiments in Figs 2c, d, g, h, k, l, and Extended Data Figs 3e and 4e. H.R. performed and analysed the experiments in Figs 2f, j, n, Extended Data Figs 5a–c, e–j, 7a and 9f–h. L.A. contributed to experiments in Fig. 3a, b and Extended Data Fig. 6a. D.M.L., W.J.P., A.M.M., C.B.M. and E.A.G. performed and analysed the experiments in Fig. 4a and Extended Data Fig. 7b, c. R.M. and G.E. designed, performed and analysed the experiments in Fig. 4b–d. H.V.-F. supervised the work, planned the experiments and wrote the manuscript.

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Correspondence to Henrique Veiga-Fernandes.

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Extended data figures and tables

Extended Data Figure 1 ILC3 selectively express the neurotrophic factor receptor RET.

a, Expression of RET protein in gut CD45+LinThy1.2hiIL7Rα+RORγt+ ILC3. b, Analysis of gut ILC3 from RetGFP mice. Embryonic day 14.5 (E14.5). c, d, Analysis of enteric ILC3 subsets from RetGFP mice. e, Analysis of cytokine-producing ILC3 from RetGFP mice. f, Pregnant RetGFP mice were provided with antibiotic cocktails that were maintained after birth until analysis at 6 weeks of age. Left, RET/GFP (white); right, flow cytometry analysis of RET/GFP expression in ILC3. Thin line, Ab-treated; bold line, specific pathogen free (SPF). g, Ret expression in enteric ILC3 from germ-free (GF) mice and SPF controls (n = 4). h, Analysis of lamina propria populations from RetGFP mice. i, Enteric ILC3 clusters. Green, RET/GFP; blue, RORγt; red, B220. Bottom, quantification analysis for RET/GFP and RORγt co-expression (79.97 ± 4.72%). j, Rare RET-expressing ILC3 in intestinal villi. Green, RET/GFP; blue, RORγt; red, CD3ε. Scale bars, 10μm. Data are representative of 4 independent experiments. Error bars show s.e.m.

Extended Data Figure 2 T cell-derived IL-22 and IL-17 in RetGFP chimaeras and RetMEN2B mice.

a, T-cell-derived IL-17 in RetGFP chimaeras. RetWT/GFP, n = 25; RetGFP/GFP, n = 22. b, T-cell-derived IL-22 and IL-17 in the intestine of RetMEN2B mice and their wild-type littermate controls (n = 7). Data are representative of 4 independent experiments. Error bars show s.e.m.

Extended Data Figure 3 Enteric homeostasis in steady-state RetΔ mice.

a, Rorgt-Cre mice were bread to Rosa26YFP mice. Analysis of Rosa26/YFP expression in gut ILC3 from Rorgt-CreRosa26YFP mice. b, Number of Peyer’s patches (PP) (n = 10). c, T-cell-derived IL-22 in RetΔ mice and their wild-type littermate controls. (n = 11). d, γδ T-cell-derived IL-22 in RetΔ mice and their wild-type littermate controls (n = 4). e, Intestinal villus and crypt morphology (n = 6). f, Epithelial cell proliferation (n = 5). g, Intestinal paracellular permeability measured by Dextran-Fitc in the plasma (n = 5). h, Tissue repair genes in RetΔ intestinal epithelium in comparison to their wild-type littermate controls (n = 8). i, Reactivity genes in RetMEN2B mice treated with anti-IL-22 blocking antibodies compared to RetMEN2B intestinal epithelium. RetMEN2B, n = 4; RetMEN2B + anti-IL-22, n = 4. Data are representative of 3 independent experiments. Error bars show s.e.m.

Extended Data Figure 4 Enteric inflammation in mice with altered RET signals.

Mice were treated with DSS in the drinking water. a, Weight loss of DSS-treated RetΔ mice and their littermate controls (n = 8). b, T-cell-derived IL-22 in RetΔ mice and their wild-type littermate controls after DSS treatment (n = 8). c, Weight loss of DSS treated RetMEN2B mice and their wild-type littermate controls (n = 8). d, T-cell-derived IL-22 in RetMEN2B mice and their wild-type littermate controls (n = 8). e, Intestinal villi and crypt morphology (n = 6). f, Epithelial reactivity gene expression in DSS treated RetΔ mice in comparison to their wild-type littermate controls (n = 8). g, Tissue repair gene expression in DSS treated RetΔ mice in comparison to their wild-type littermate controls (n = 4). Data are representative of 3–4 independent experiments. Error bars show s.e.m. *P < 0.05; **P < 0.01.

Extended Data Figure 5 Citrobacter rodentium infection in RetΔ mice.

a, C. rodentium translocation to the liver of Rag1−/−RetΔ and their Rag1−/−Retfl littermate controls at day 6 after infection (n = 15). b, MacConkey plates of liver cell suspensions from Rag1−/−RetΔ and their Rag1−/−Retfl littermate controls at day 6 after C. rodentium infection. c, Whole-body imaging of Rag1−/−RetΔ and their Rag1−/−Retfl littermate controls at day 6 after luciferase-expressing C. rodentium infection. d, Epithelial reactivity gene expression in C. rodentium infected Rag1−/−RetΔ mice (n = 17) and their Rag1−/−Retfl littermate controls (n = 15). e, Weight loss in C. rodentium-infected Rag1−/−RetΔ mice and their Rag1−/−Retfl littermate controls (n = 8). f, Survival curves in C. rodentium infected Rag1−/−RetΔ mice and their Rag1−/−Retfl littermate controls (n = 8). g, C. rodentium translocation to the liver of RetΔ and their Retfl littermate controls at day 6 after infection (n = 6). h, MacConkey plates of liver cell suspensions from RetΔ and their Retfl littermate controls at day 6 after C. rodentium infection. i, Whole-body imaging of RetΔ and their Retfl littermate controls at day 6 after luciferase-expressing C. rodentium infection. j, C. rodentium infection burden (n = 8). k, Innate IL-22 in in C. rodentium infected RetΔ mice and their Retfl littermate controls (n = 8). Data are representative of 3–4 independent experiments. Error bars show s.e.m. ns, not significant. *P < 0.05; **P < 0.01.

Extended Data Figure 6 Glial-derived neurotrophic factor family ligand (GFL) signals in ILC3.

a, Multi-tissue intestinal organoid system. Scale bar, 20μm. Black arrows, ILC3. b, Expression of ILC-related genes in ILC3 from RetΔ mice in comparison to their littermate controls (n = 4). c, ILC3 activation with all GFL/GFRα pairs (GFL); single GDNF family ligand (GDNF, ARTN or NRTN); or single GFL/GFRα pairs (GDNF/GFRα1, ARTN/GFRα3 or NRTN/GFRα2) compared to vehicle BSA (n = 5). d, ILC3 from RetΔ mice (open black) and their littermate controls (open dash). Isotype (closed grey). e, 30-min activation of ILC3 by GFL (open black) compared to vehicle BSA (open dash). Isotype (closed grey). f, 10-min activation of ILC3 by GFL. pERK, n = 8; pAKT, n = 8; phosphorylated p38/MAP kinase, n = 8; pSTAT3, n = 8. Similar results were obtained in at least 3–4 independent experiments. Error bars show s.e.m. *P < 0.05; **P < 0.01.

Extended Data Figure 7 Alterations in the diversity of intestinal commensal bacteria of RetΔ mice.

a, Quantitative PCR analysis at the phylum level in stool bacteria from co-housed Retfl and RetΔ littermates in steady state (n = 5). b, Metagenomic phylum level comparisons in stool bacterial from co-housed Retfl and RetΔ littermates in steady state (left) and after DSS treatment (right) (n = 5). c, Genus-level comparisons in stool bacteria from co-housed Retfl and RetΔ littermates in steady state (left) and after DSS treatment (right) (n = 5). Error bars show s.e.m. *P < 0.05; **P < 0.01.

Extended Data Figure 8 GFL-expressing glial cells anatomically co-localize with ILC3.

a, Intestine of RetGFP mice. Green, RET/GFP; red, GFAP; blue, RORγt. Similar results were obtained in 3 independent experiments. b, Purified lamina propria LTi, NCR and NCR+ ILC3 subsets, T cells (T), B cells (B), dendritic cells (Dc), macrophages (Mø), enteric neurons (N) and mucosal glial cells (G). c, Neurosphere-derived glial cells. d, Activation of neurosphere-derived glial cells with TLR2 (Pam3CSK4), TLR3 (Poli I:C), TLR4 (LPS) and TLR9 (DsDNA-EC) ligands, as well as IL-1β, IL-18 and IL-33 (n = 6). M, medium. e, Il22 in co-cultures of glial and ILC3 using single or combined GFL antagonists (n = 6). f, Il22 in co-cultures of ILC3 and glial cells from Il1b−/− or their wild-type controls (n = 3). g, Gdnf, Artn and Nrtn expression in glial cells and ILC3 upon TLR2 stimulation (n = 3). Scale bar, 30 μm. Similar results were obtained in at least 4 independent experiments.

Extended Data Figure 9 Glial cell sensing via MYD88 signals.

ac, Intestinal glial cells were purified by flow cytometry. a, Germ-free and their respective SPF controls (n = 3). b, Myd88−/− and their respective wild-type littermate controls (n = 3). c, Gfap-CreMyd88Δ and their littermate controls (Myd88fl) (n = 3). d, Total lamina propria cells of Gfap-CreMyd88Δ and their littermate controls (Myd88fl) (n = 6). eh , Citrobacter rodentium infection of Gfap-CreMyd88Δ mice and their littermate controls (Myd88fl) (n = 6). e, Innate IL-22. f, Citrobacter rodentium translocation. g, Infection burden. h, Weight loss. Data are representative of 3 independent experiments. Error bars show s.e.m. *P < 0.05; **P < 0.01.

Extended Data Figure 10 A novel glial-ILC3-epithelial cell unit orchestrated by neurotrophic factors.

Lamina propria glial cells sense microenvironmental products that control neurotrophic factor expression. Glial-derived neurotrophic factors operate in an ILC3-intrinsic manner by activating the tyrosine kinase RET, which directly regulates innate IL-22 downstream of a p38 MAPK/ERK-AKT cascade and STAT3 phosphorylation. GFL induced innate IL-22 acts on epithelial cells to induce reactivity gene expression (CBP, commensal bacterial products; AMP, antimicrobial peptides; Muc, mucins). Thus, neurotrophic factors are the molecular link between glial cell sensing, innate IL-22 production and intestinal epithelial barrier defence.

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Ibiza, S., García-Cassani, B., Ribeiro, H. et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535, 440–443 (2016). https://doi.org/10.1038/nature18644

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