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Type 3 innate lymphoid cell-derived lymphotoxin prevents microbiota-dependent inflammation

Cellular & Molecular Immunology volume 15, pages 697–709 (2018)Cite this article

Abstract

Splenomegaly is a well-known phenomenon typically associated with inflammation. However, the underlying cause of this phenotype has not been well characterized. Furthermore, the splenomegaly phenotype seen in lymphotoxin (LT) signaling-deficient mice is characterized by increased numbers of splenocytes and splenic neutrophils. Splenomegaly, as well as the related phenotype of increased lymphocyte counts in non-lymphoid tissues, is thought to result from the absence of secondary lymphoid tissues in LT-deficient mice. We now present evidence that mice deficient in LTα1β2 or LTβR develop splenomegaly and increased numbers of lymphocytes in non-lymphoid tissues in a microbiota-dependent manner. Antibiotic administration to LTα1β2- or LTβR-deficient mice reduces splenomegaly. Furthermore, re-derived germ-free Ltbr −/− mice do not exhibit splenomegaly or increased inflammation in non-lymphoid tissues compared to specific pathogen-free Ltbr −/− mice. By using various LTβ- and LTβR-conditional knockout mice, we demonstrate that retinoic acid-related orphan receptor γT-positive type 3 innate lymphoid cells provide the required active LT signaling to prevent the development of splenomegaly. Thus, this study demonstrates the importance of LT-mediated immune responses for the prevention of splenomegaly and systemic inflammation induced by microbiota.

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References

  1. Consortium THMP. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486: 207–214.

    Article  Google Scholar 

  2. Hooper LV, Macpherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol 2010; 10: 159–169.

    Article  CAS  Google Scholar 

  3. Smith K, McCoy KD, Macpherson AJ. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol 2007; 19: 59–69.

    Article  CAS  Google Scholar 

  4. Eberl G, Marmon S, Sunshine M-J, Rennert PD, Choi Y, Littman DR. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat Immunol 2004; 5: 64–73.

    Article  CAS  Google Scholar 

  5. Sonnenberg GF, Artis D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med 2015; 21: 698–708.

    Article  CAS  Google Scholar 

  6. Sonnenberg GF. Regulation of intestinal health and disease by innate lymphoid cells. Int Immunol 2014; 26: 501–507.

    Article  CAS  Google Scholar 

  7. Sawa S, Lochner M, Satoh-Takayama N, Dulauroy S, Bérard M, Kleinschek M et al. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat Immunol 2011; 12: 320–326.

    Article  CAS  Google Scholar 

  8. Hepworth MR, Fung TC, Masur SH, Kelsen JR, McConnell FM, Dubrot J et al. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science 2015; 348: 1031–1035.

    Article  CAS  Google Scholar 

  9. Berger DP, Naniche D, Crowley MT, Koni PA, Flavell RA, Oldstone MBA. Lymphotoxin-β-deficient mice show defective antiviral immunity. Virology 1999; 260: 136–147.

    Article  CAS  Google Scholar 

  10. GeurtsvanKessel CH, Willart MAM, Bergen IM, van Rijt LS, Muskens F, Elewaut D et al. Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J Exp Med 2009; 206: 2339–2349.

    Article  CAS  Google Scholar 

  11. Kumar V, Scandella E, Danuser R, Onder L, Nitschké M, Fukui Y et al. Global lymphoid tissue remodeling during a viral infection is orchestrated by a B cell-lymphotoxin-dependent pathway. Blood 2010; 115: 4725–4733.

    Article  CAS  Google Scholar 

  12. Macpherson AJ, Gatto D, Sainsbury E, Harriman GR, Hengartner H, Zinkernagel RM. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 2000; 288: 2222–2226.

    Article  CAS  Google Scholar 

  13. Ota N, Wong K, Valdez PA, Zheng Y, Crellin NK, Diehl L et al. IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nat Immunol 2011; 12: 941–948.

    Article  CAS  Google Scholar 

  14. Tumanov AV, Kuprash DV, Lagarkova MA, Grivennikov SI, Abe K, Shakhov AN et al. Distinct role of surface lymphotoxin expressed by B cells in the organization of secondary lymphoid tissues. Immunity 2002; 17: 239–250.

    Article  CAS  Google Scholar 

  15. Upadhyay V, Fu Y-X. Lymphotoxin signalling in immune homeostasis and the control of microorganisms. Nat Rev Immunol 2013; 13: 270–279.

    Article  CAS  Google Scholar 

  16. Ware CF, VanArsdale TL, Crowe PD, Browning JL. The ligands and receptors of the lymphotoxin system. Curr Top Microbiol Immunol 1995; 198: 175–218.

    CAS  PubMed  Google Scholar 

  17. Alimzhanov MB, Kuprash DV, Kosco-Vilbois MH, Luz A, Turetskaya RL, Tarakhovsky A et al. Abnormal development of secondary lymphoid tissues in lymphotoxin β-deficient mice. Proc Natl Acad Sci USA 1997; 94: 9302–9307.

    Article  CAS  Google Scholar 

  18. De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 1994; 264: 703–707.

    Article  CAS  Google Scholar 

  19. Fütterer A, Mink K, Luz A, Kosco-Vilbois MH, Pfeffer K. The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 1998; 9: 59–70.

    Article  Google Scholar 

  20. Mariathasan S, Matsumoto M, Baranyay F, Nahm MH, Kanagawa O, Chaplin DD. Absence of lymph nodes in lymphotoxin-alpha(LT alpha)-deficient mice is due to abnormal organ development, not defective lymphocyte migration. J Inflamm 1995; 45: 72–78.

    CAS  PubMed  Google Scholar 

  21. Tumanov AV, Grivennikov SI, Shakhov AN, Rybtsov SA, Koroleva EP, Takeda J et al. Dissecting the role of lymphotoxin in lymphoid organs by conditional targeting. Immunol Rev 2003; 195: 106–116.

    Article  CAS  Google Scholar 

  22. Onder L, Danuser R, Scandella E, Firner S, Chai Q, Hehlgans T et al. Endothelial cell-specific lymphotoxin-β receptor signaling is critical for lymph node and high endothelial venule formation. J Exp Med 2013; 210: 465–473.

    Article  CAS  Google Scholar 

  23. Fu Y-X, Chaplin DD. Development and maturation of secondary lymphoid tissues. Annu Rev Immunol 1999; 17: 399–433.

    Article  CAS  Google Scholar 

  24. van de Pavert SA, Mebius RE. New insights into the development of lymphoid tissues. Nat Rev Immunol 2010; 10: 664–674.

    Article  CAS  Google Scholar 

  25. Mullighan CG, Fanning GC, Chapel HM, Welsh KI. TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease. J Immunol 1997; 159: 6236–6241.

    CAS  PubMed  Google Scholar 

  26. Richard AC, Peters JE, Lee JC, Vahedi G, Schäffer AA, Siegel RM et al. Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network. Genome Med 2016 [Internet]. 2016 Jul 19 (cited 2016 Aug 8);8. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4952362/.

  27. Mackay F, Majeau GR, Lawton P, Hochman PS, Browning JL. Lymphotoxin but not tumor necrosis factor functions to maintain splenic architecture and humoral responsiveness in adult mice. Eur J Immunol 1997; 27: 2033–2042.

    Article  CAS  Google Scholar 

  28. Kang H-S, Blink SE, Chin RK, Lee Y, Kim O, Weinstock J et al. Lymphotoxin Is required for maintaining physiological levels of serum IgE that minimizes Th1-mediated airway inflammation. J Exp Med 2003; 198: 1643–1652.

    Article  CAS  Google Scholar 

  29. Spahn TW, Müller MK, Domschke W, Kucharzik T. Role of lymphotoxins in the development of Peyer’s patches and mesenteric lymph nodes. Ann NY Acad Sci 2006; 1072: 187–193.

    Article  CAS  Google Scholar 

  30. Zhu M, Yang Y, Wang Y, Wang Z, Fu Y-X. LIGHT regulates inflamed draining lymph node hypertrophy. J Immunol 2011; 186: 7156–7163.

    Article  CAS  Google Scholar 

  31. Browning JL, Allaire N, Ngam-Ek A, Notidis E, Hunt J, Perrin S et al. Lymphotoxin-beta receptor signaling is required for the homeostatic control of HEV differentiation and function. Immunity 2005; 23: 539–550.

    Article  CAS  Google Scholar 

  32. Chyou S, Ekland EH, Carpenter AC, Tzeng T-CJ, Tian S, Michaud M et al. Fibroblast-type reticular stromal cells regulate the lymph node vasculature. J Immunol. 2008; 181: 3887–3896.

    Article  CAS  Google Scholar 

  33. Liao S, Ruddle NH. Synchrony of High Endothelial venules and lymphatic vessels revealed by immunization. J Immunol 2006; 177: 3369–3379.

    Article  CAS  Google Scholar 

  34. Scheu S, Alferink J, Pötzel T, Barchet W, Kalinke U, Pfeffer K. Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin beta in mesenteric lymph node genesis. J Exp Med 2002; 195: 1613–1624.

    Article  CAS  Google Scholar 

  35. Tumanov AV, Koroleva EP, Guo X, Wang Y, Kruglov A, Nedospasov S et al. Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge. Cell Host Microbe 2011; 10: 44–53.

    Article  CAS  Google Scholar 

  36. Wang Y, Koroleva EP, Kruglov AA, Kuprash DV, Nedospasov SA, Fu Y-X et al. Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 2010; 32: 403–413.

    Article  Google Scholar 

  37. DiSanto JP, Müller W, Guy-Grand D, Fischer A, Rajewsky K. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci USA 1995; 92: 377–381.

    Article  CAS  Google Scholar 

  38. 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 2004; 118: 229–241.

    Article  CAS  Google Scholar 

  39. Guo X, Qiu J, Tu T, Yang X, Deng L, Anders RA et al. Induction of innate lymphoid cell-derived interleukin-22 by the transcription factor STAT3 mediates protection against intestinal infection. Immunity 2014; 40: 25–39.

    Article  CAS  Google Scholar 

  40. Guo X, Muite K, Wroblewska J, Fu Y-XPurification and adoptive transfer of group 3 gut innate lymphoid cellsIn:Ivanov AI(ed.). Gastrointestinal Physiology and Diseases. Springer: New York, NY, USA. 2016 pp 189–196.

  41. Wu Q, Wang Y, Wang J, Hedgeman EO, Browning JL, Fu Y-X. The requirement of membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues. J Exp Med 1999; 190: 629–638.

    Article  CAS  Google Scholar 

  42. Browning JL, Sizing ID, Lawton P, Bourdon PR, Rennert PD, Majeau GR et al. Characterization of lymphotoxin-alpha beta complexes on the surface of mouse lymphocytes. J Immunol 1997; 159: 3288–3298.

    CAS  PubMed  Google Scholar 

  43. Johansson MEV, Jakobsson HE, Holmén-Larsson J, Schütte A, Ermund A, Rodríguez-Piñeiro AM et al. Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe 2015; 18: 582–592.

    Article  CAS  Google Scholar 

  44. Costello EK, Stagaman K, Dethlefsen L, Bohannan BJM, Relman DA. The application of ecological theory toward an understanding of the human microbiome. Science 2012; 336: 1255–1262.

    Article  CAS  Google Scholar 

  45. Sonnenberg GF, Monticelli LA, Alenghat T, Fung TC, Hutnick NA, Kunisawa J et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 2012; 336: 1321–1325.

    Article  CAS  Google Scholar 

  46. Lee J-Y, Ristow M, Lin X, White MF, Magnuson MA, Hennighausen L. RIP-Cre revisited, evidence for impairments of pancreatic β-cell function. J Biol Chem 2006; 281: 2649–2653.

    Article  CAS  Google Scholar 

  47. Smith L. Good planning and serendipity: exploiting the Cre/Lox system in the testis. Reproduction 2011; 141: 151–161.

    Article  CAS  Google Scholar 

  48. Garcia S, DiSanto J, Stockinger B. Following the development of a CD4 T cell response in vivo. Immunity 1999; 11: 163–171.

    Article  CAS  Google Scholar 

  49. Greenberg PD, Riddell SR. Deficient Cellular Immunity—finding and fixing the defects. Science 1999; 285: 546–551.

    Article  CAS  Google Scholar 

  50. Garidou L, Pomié C, Klopp P, Waget A, Charpentier J, Aloulou M et al. The gut microbiota regulates intestinal CD4 T cells expressing RORγt and controls metabolic disease. Cell Metab 2015; 22: 100–112.

    Article  CAS  Google Scholar 

  51. Zhang N, Guo J, He Y-W. Lymphocyte accumulation in the spleen of retinoic acid receptor-related orphan receptor gamma-deficient mice. J Immunol 2003; 171: 1667–1675.

    Article  CAS  Google Scholar 

  52. Hepworth MR, Monticelli LA, Fung TC, Ziegler CGK, Grunberg S, Sinha R et al. Innate lymphoid cells regulate CD4+ T cell responses to intestinal commensal bacteria. Nature 2013; 498: 113–117.

    Article  CAS  Google Scholar 

  53. Ehlers S, Holscher C, Scheu S, Tertilt C, Hehlgans T, Suwinski J et al. The Lymphotoxin Receptor Is Critically Involved in Controlling Infections with the Intracellular Pathogens Mycobacterium tuberculosis and Listeria monocytogenes. J Immunol. 2003; 170: 5210–5218.

    Article  CAS  Google Scholar 

  54. Hu D, Mohanta SK, Yin C, Peng L, Ma Z, Srikakulapu P et al. Artery tertiary lymphoid organs control aorta immunity and protect against atherosclerosis via vascular smooth muscle cell lymphotoxin β receptors. Immunity 2015; 42: 1100–1115.

    Article  CAS  Google Scholar 

  55. Schneider K, Loewendorf A, De Trez C, Fulton J, Rhode A, Shumway H et al. Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe 2008; 3: 67–76.

    Article  CAS  Google Scholar 

  56. Sun T, Rojas OL, Li C, Philpott DJ, Gommerman JL. Hematopoietic LTβR deficiency results in skewed T cell cytokine profiles during a mucosal viral infection. J Leukoc Biol 2016; 100: 103–110.

    Article  CAS  Google Scholar 

  57. Spahn TW, Maaser C, Eckmann L, Heidemann J, Lügering A, Newberry R et al. The lymphotoxin-β receptor is critical for control of murine Citrobacter rodentium-induced colitis. Gastroenterology 2004; 127: 1463–1473.

    Article  CAS  Google Scholar 

  58. Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 2008; 14: 282–289.

    Article  CAS  Google Scholar 

  59. Peterson DA, Planer JD, Guruge JL, Xue L, Downey-Virgin W, Goodman AL et al. Characterizing the interactions between a naturally primed immunoglobulin A and its conserved Bacteroides thetaiotaomicron species-specific epitope in gnotobiotic mice. J Biol Chem 2015; 290: 12630–12649.

    Article  CAS  Google Scholar 

  60. Deplancke B, Gaskins HR. Microbial modulation of innate defense: goblet cells and the intestinal mucus layer. Am J Clin Nutr 2001; 73: 1131S–1141S.

    Article  CAS  Google Scholar 

  61. Loonen LMP, Stolte EH, Jaklofsky MTJ, Meijerink M, Dekker J, van Baarlen P et al. REG3γ-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum. Mucosal Immunol 2014; 7: 939–947.

    Article  CAS  Google Scholar 

  62. Specian RD, Oliver MG. Functional biology of intestinal goblet cells. Am J Physiol 1991; 260: C183–C193.

    Article  CAS  Google Scholar 

  63. Fung TC, Bessman NJ, Hepworth MR, Kumar N, Shibata N, Kobuley D et al. Lymphoid-tissue-resident commensal bacteria promote members of the IL-10 cytokine family to establish mutualism. Immunity 2016; 44: 634–646.

    Article  CAS  Google Scholar 

  64. Withers DR, Hepworth MR, Wang X, Mackley EC, Halford EE, Dutton EE et al. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nat Med 2016; 22: 319–323.

    Article  CAS  Google Scholar 

  65. Sonnenberg GF, Monticelli LA, Elloso MM, Fouser LA, Artis D. CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 2011; 34: 122–134.

    Article  CAS  Google Scholar 

  66. Sonnenberg GF, Fouser LA, Artis D. Functional biology of the IL-22-IL-22R pathway in regulating immunity and inflammation at barrier surfaces. Adv Immunol 2010; 107: 1–29.

    Article  CAS  Google Scholar 

  67. Pham TAN, Clare S, Goulding D, Arasteh JM, Stares MD, Browne HP et al. Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. Cell Host Microbe 2014; 16: 504–516.

    Article  CAS  Google Scholar 

  68. Satoh-Takayama N, Lesjean-Pottier S, Sawa S, Vosshenrich CAJ, Eberl G, Di Santo JP. Lymphotoxin-β receptor-independent development of intestinal IL-22-producing NKp46+ innate lymphoid cells. Eur J Immunol 2011; 41: 780–786.

    Article  CAS  Google Scholar 

  69. Zenewicz LA, Yin X, Wang G, Elinav E, Hao L, Zhao L et al. IL-22 Deficiency alters colonic microbiota to be transmissible and colitogenic. J Immunol 2013; 190: 5306–5312.

    Article  CAS  Google Scholar 

  70. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 2008; 29: 947–957.

    Article  CAS  Google Scholar 

  71. Tang H, Zhu M, Qiao J, Fu Y-X. Lymphotoxin signalling in tertiary lymphoid structures and immunotherapy. Cell Mol Immunol 2017 Available at http://www.nature.com/doifinder/10.1038/cmi.2017.13 (accessed on 28 April 2017).

    Article  PubMed  PubMed Central  Google Scholar 

  72. McHugh NJ, Owen P, Cox B, Dunphy J, Welsh K. MHC class II, tumour necrosis factor alpha, and lymphotoxin alpha gene haplotype associations with serological subsets of systemic lupus erythematosus. Ann Rheum Dis 2006; 65: 488–494.

    Article  CAS  Google Scholar 

  73. Stemme S, Fager G, Hansson GK. MHC class II antigen expression in human vascular smooth muscle cells is induced by interferon-gamma and modulated by tumour necrosis factor and lymphotoxin. Immunology 1990; 69: 243–249.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang J, Fu Y-X. LIGHT (a cellular ligand for herpes virus entry mediator and lymphotoxin receptor)-mediated thymocyte deletion is dependent on the interaction between TCR and MHC/self-peptide. J Immunol 2003; 170: 3986–3993.

    Article  CAS  Google Scholar 

  75. Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol2011 12: 383–390.

    Article  CAS  Google Scholar 

  76. Lorenz RG, Chaplin DD, McDonald KG, McDonough JS, Newberry RD. Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient b lymphocytes, lymphotoxin β receptor, and TNF receptor I function. J Immunol 2003; 170: 5475–5482.

    Article  CAS  Google Scholar 

  77. Giacomin PR, Moy RH, Noti M, Osborne LC, Siracusa MC, Alenghat T et al. Epithelial-intrinsic IKK expression regulates group 3 innate lymphoid cell responses and antibacterial immunity. J Exp Med 2015; 212: 1513–1528.

    Article  CAS  Google Scholar 

  78. Mortha A, Chudnovskiy A, Hashimoto D, Bogunovic M, Spencer SP, Belkaid Y et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 2014; 343: 1249288.

    Article  Google Scholar 

  79. Qiu J, Guo X, Chen Z-ME, He L, Sonnenberg GF, Artis D et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 2013; 39: 386–399.

    Article  CAS  Google Scholar 

  80. Sanos SL, Vonarbourg C, Mortha A, Diefenbach A. Control of epithelial cell function by interleukin-22-producing RORγt+ innate lymphoid cells. Immunology 2011; 132: 453–465.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Cathy Nagler from University of Chicago for insightful discussions. We thank Andrea Crawford and Dr Betty Theriault from Gnotobiotic Research Animal Facility at University of Chicago for technical assistance with our germ-free mouse colony.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, University of Chicago, 60637, Chicago, USA, IL

    Yuan Zhang, Tae-Jin Kim, Vera Tesic & Yang-Xin Fu

  2. Department of Biochemistry and Molecular Biology, Korea University College of Medicine, 02841, Seoul, Korea

    Tae-Jin Kim

  3. Committee on Immunology, Department of Pathology, University of Chicago, 60637, Chicago, IL, USA

    Joanna A Wroblewska & Vaibhav Upadhyay

  4. Department of Radiation and Cellular Oncology and The Ludwig Center for Metastasis Research, University of Chicago, 60637, Chicago, IL, USA

    Ralph R Weichselbaum

  5. Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center San Antonio, 78229, San Antonio, TX, USA

    Alexei V Tumanov

  6. Chinese Academy of Sciences Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China

    Hong Tang

  7. Institute of Immunology, Tsinghua University School of Medicine, 100084, Beijing, China

    Xiaohuan Guo

  8. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Haidong Tang & Yang-Xin Fu

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  1. Yuan Zhang
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Zhang, Y., Kim, TJ., Wroblewska, J. et al. Type 3 innate lymphoid cell-derived lymphotoxin prevents microbiota-dependent inflammation. Cell Mol Immunol 15, 697–709 (2018). https://doi.org/10.1038/cmi.2017.25

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