Eosinophils suppress Th1 responses and restrict bacterially induced gastrointestinal inflammation

Eosinophils are predominantly known for their contribution to allergy. Here, we have examined the function and regulation of gastrointestinal eosinophils in the steady-state and during infection with Helicobacter pylori or Citrobacter rodentium. We find that eosinophils are recruited to sites of infection, directly encounter live bacteria, and activate a signature transcriptional program; this applies also to human gastrointestinal eosinophils in humanized mice. The genetic or anti–IL-5–mediated depletion of eosinophils results in improved control of the infection, increased inflammation, and more pronounced Th1 responses. Eosinophils control Th1 responses via the IFN-&ggr;–dependent up-regulation of PD-L1. Furthermore, we find that the conditional loss of IFN-&ggr;R in eosinophils phenocopies the effects of eosinophil depletion. Eosinophils further possess bactericidal properties that require their degranulation and the deployment of extracellular traps. Our results highlight two novel functions of this elusive cell type and link it to gastrointestinal homeostasis and anti-bacterial defense.

[1]  K. Ottemann,et al.  NLRP3 Controls the Development of Gastrointestinal CD11b+ Dendritic Cells in the Steady State and during Chronic Bacterial Infection. , 2017, Cell reports.

[2]  K. Ottemann,et al.  Spatial and Temporal Shifts in Bacterial Biogeography and Gland Occupation during the Development of a Chronic Infection , 2016, mBio.

[3]  M. Rothenberg,et al.  The Regulatory Function of Eosinophils , 2016, Microbiology spectrum.

[4]  M. Thiry,et al.  Lung-resident eosinophils represent a distinct regulatory eosinophil subset. , 2016, The Journal of clinical investigation.

[5]  You-Me Kim,et al.  Small intestinal eosinophils regulate Th17 cells by producing IL-1 receptor antagonist , 2016, The Journal of experimental medicine.

[6]  F. Powrie,et al.  Granulocyte Macrophage Colony-Stimulating Factor-Activated Eosinophils Promote Interleukin-23 Driven Chronic Colitis , 2015, Immunity.

[7]  G. Eberl,et al.  Addressing the experimental variability associated with the microbiota , 2015, Mucosal Immunology.

[8]  Garth J. Williams,et al.  Toxicity of eosinophil MBP is repressed by intracellular crystallization and promoted by extracellular aggregation. , 2015, Molecular cell.

[9]  Eh Lee,et al.  IL-1β in eosinophil-mediated small intestinal homeostasis and IgA production , 2014, Mucosal Immunology.

[10]  M. Rothenberg,et al.  Roles and Regulation of Gastrointestinal Eosinophils in Immunity and Disease , 2014, The Journal of Immunology.

[11]  C. Berek,et al.  Eosinophils promote generation and maintenance of immunoglobulin-A-expressing plasma cells and contribute to gut immune homeostasis. , 2014, Immunity.

[12]  James J. Lee,et al.  Homologous recombination into the eosinophil peroxidase locus generates a strain of mice expressing Cre recombinase exclusively in eosinophils , 2013, Journal of leukocyte biology.

[13]  D. Littman,et al.  Microbiota Restrict Trafficking of Bacteria to Mesenteric Lymph Nodes by CX3CR1hi Cells , 2013, Nature.

[14]  C. Berek,et al.  The establishment of the plasma cell survival niche in the bone marrow , 2013, Immunological reviews.

[15]  K. Dyer,et al.  Eosinophils: changing perspectives in health and disease , 2012, Nature Reviews Immunology.

[16]  James J. Lee,et al.  The development of a sensitive and specific ELISA for mouse eosinophil peroxidase: assessment of eosinophil degranulation ex vivo and in models of human disease. , 2012, Journal of immunological methods.

[17]  V. DiRita,et al.  Faculty Opinions recommendation of Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells. , 2011 .

[18]  M. Lopes,et al.  Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells , 2011, Proceedings of the National Academy of Sciences.

[19]  S. Arandjelovic,et al.  PAD4-Mediated Neutrophil Extracellular Trap Formation Is Not Required for Immunity against Influenza Infection , 2011, PloS one.

[20]  R. Locksley,et al.  Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose Homeostasis , 2011, Science.

[21]  R. Flavell,et al.  Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia. , 2011, Gastroenterology.

[22]  James J. Lee,et al.  Mouse Eosinophils Possess Potent Antibacterial Properties In Vivo , 2009, Infection and Immunity.

[23]  H. Rehrauer,et al.  The CD4+ T Cell-Mediated IFN-γ Response to Helicobacter Infection Is Essential for Clearance and Determines Gastric Cancer Risk1 , 2009, The Journal of Immunology.

[24]  V. Nizet,et al.  Innate immunity turned inside-out: antimicrobial defense by phagocyte extracellular traps , 2009, Journal of Molecular Medicine.

[25]  S. Siegel,et al.  Functionally Competent Eosinophils Differentiated Ex Vivo in High Purity from Normal Mouse Bone Marrow1 , 2008, The Journal of Immunology.

[26]  A. Straumann,et al.  Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense , 2008, Nature Medicine.

[27]  Masahiko Kato,et al.  Interferon-gamma enhances human eosinophil effector functions induced by granulocyte-macrophage colony-stimulating factor or interleukin-5. , 2008, Immunology letters.

[28]  Roland Hartig,et al.  Helicobacter exploits integrin for type IV secretion and kinase activation , 2007, Nature.

[29]  Steffen Jung,et al.  A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration , 2005, Nature Methods.

[30]  N. Talley,et al.  Eosinophil infiltration and degranulation inHelicobacter pylori-associated chronic gastritis , 1991, Digestive Diseases and Sciences.

[31]  A. Borazan,et al.  Eosinophil infiltration, gastric juice and serum eosinophil cationic protein levels in Helicobacter pylori-associated chronic gastritis and gastric ulcer. , 2004, Mediators of inflammation.

[32]  E. Lenkiewicz,et al.  Defining a Link with Asthma in Mice Congenitally Deficient in Eosinophils , 2004, Science.

[33]  F. Wolber,et al.  Roles of spleen and liver in development of the murine hematopoietic system. , 2002, Experimental hematology.

[34]  J. Pollard,et al.  Eotaxin Is Required for Eosinophil Homing into the Stroma of the Pubertal and Cycling Uterus. , 2001, Endocrinology.

[35]  A. Herbelin,et al.  CD11c+ Eosinophils in the Murine Thymus: Developmental Regulation and Recruitment upon MHC Class I-Restricted Thymocyte Deletion , 2000, The Journal of Immunology.

[36]  E. Hahn,et al.  Secretion and tissue content of eosinophil cationic protein in Crohn's disease. , 2000, Journal of clinical gastroenterology.

[37]  K. Dyer,et al.  Eosinophil Cationic Protein and Eosinophil-derived Neurotoxin , 1995, Journal of Biological Chemistry.

[38]  T. Ganz,et al.  Antibacterial properties of eosinophil major basic protein and eosinophil cationic protein. , 1989, Journal of immunology.