The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1)

Schistosoma mansoni eggs contain factors that trigger potent Th2 responses in vivo and condition mouse dendritic cells (DCs) to promote Th2 lymphocyte differentiation. Using an in vitro bystander polarization assay as the readout, we purified and identified the major Th2-inducing component from soluble egg extract (SEA) as the secreted T2 ribonuclease, omega-1. The Th2-promoting activity of omega-1 was found to be sensitive to ribonuclease inhibition and did not require MyD88/TRIF signaling in DCs. In common with unfractioned SEA, the purified native protein suppresses lipopolysaccharide-induced DC activation, but unlike SEA, it fails to trigger interleukin 4 production from basophils. Importantly, omega-1–exposed DCs displayed pronounced cytoskeletal changes and exhibited decreased antigen-dependent conjugate formation with CD4+ T cells. Based on this evidence, we hypothesize that S. mansoni omega-1 acts by limiting the interaction of DCs with CD4+ T lymphocytes, thereby lowering the strength of the activation signal delivered.

[1]  B. Everts,et al.  Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses , 2009, The Journal of experimental medicine.

[2]  J. Dalton,et al.  Helminth 2‐Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  F. Klauschen,et al.  SAP-controlled T-B cell interactions underlie germinal centre formation , 2008, Nature.

[4]  W. Paul,et al.  CD4 T cells: fates, functions, and faults. , 2008, Blood.

[5]  Ruslan Medzhitov,et al.  A mechanism for the initiation of allergen-induced T helper type 2 responses , 2008, Nature Immunology.

[6]  H. Rosenberg,et al.  Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2–MyD88 signal pathway in dendritic cells and enhances Th2 immune responses , 2008, The Journal of experimental medicine.

[7]  R. Medzhitov.  Recognition of microorganisms and activation of the immune response , 2007, Nature.

[8]  M. Joshi,et al.  Molecular and Functional Analyses of a Novel Class I Secretory Nuclease from the Human Pathogen, Leishmania donovani* , 2007, Journal of Biological Chemistry.

[9]  S. Jenkins,et al.  Dendritic cell activation and function in response to Schistosoma mansoni. , 2006, International journal for parasitology.

[10]  M. Bar‐eli,et al.  ACTIBIND, an actin‐binding fungal T2‐RNase with antiangiogenic and anticarcinogenic characteristics , 2006, Cancer.

[11]  C. Grevelding,et al.  Molecular characterization of omega-1: a hepatotoxic ribonuclease from Schistosoma mansoni eggs. , 2005, Molecular and biochemical parasitology.

[12]  N. Pavelka,et al.  Double-stranded RNAs from the Helminth Parasite Schistosoma Activate TLR3 in Dendritic Cells* , 2005, Journal of Biological Chemistry.

[13]  Jie Sun,et al.  Helminth Antigens Modulate TLR-Initiated Dendritic Cell Activation1 , 2004, The Journal of Immunology.

[14]  E. Pearce,et al.  Th2 response polarization during infection with the helminth parasite Schistosoma mansoni , 2004, Immunological reviews.

[15]  A. Sher,et al.  Parasite-Induced Th2 Polarization Is Associated with Down-Regulated Dendritic Cell Responsiveness to Th1 Stimuli and a Transient Delay in T Lymphocyte Cycling , 2004, The Journal of Immunology.

[16]  Paul G. Thomas,et al.  Maturation of Dendritic Cell 2 Phenotype by a Helminth Glycan Uses a Toll-Like Receptor 4-Dependent Mechanism 1 , 2003, The Journal of Immunology.

[17]  S. Haeryfar,et al.  Cutting Edge: Dendritic Cell Actin Cytoskeletal Polarization during Immunological Synapse Formation Is Highly Antigen-Dependent 1 , 2003, The Journal of Immunology.

[18]  S. Akira,et al.  Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway , 2003, Science.

[19]  Franco H Falcone,et al.  Molecular Characterization of an Interleukin-4-inducing Factor from Schistosoma mansoni Eggs* , 2003, The Journal of Biological Chemistry.

[20]  I. Wilson,et al.  Schistosome N‐glycans containing core α3‐fucose and core β2‐xylose epitopes are strong inducers of Th2 responses in mice , 2003 .

[21]  J. Brouwers,et al.  A Novel Host-Parasite Lipid Cross-talk , 2002, The Journal of Biological Chemistry.

[22]  A. Sher,et al.  In the absence of IL-12, CD4(+) T cell responses to intracellular pathogens fail to default to a Th2 pattern and are host protective in an IL-10(-/-) setting. , 2002, Immunity.

[23]  Yuetsu Tanaka,et al.  Microbial Compounds Selectively Induce Th1 Cell-Promoting or Th2 Cell-Promoting Dendritic Cells In Vitro with Diverse Th Cell-Polarizing Signals1 , 2002, The Journal of Immunology.

[24]  E. Pearce,et al.  Cutting Edge: Th2 Response Induction by Dendritic Cells: A Role for CD401 , 2002, The Journal of Immunology.

[25]  E. Pearce,et al.  CD8− Dendritic Cell Activation Status Plays an Integral Role in Influencing Th2 Response Development1 , 2001, The Journal of Immunology.

[26]  P. Ashton,et al.  The schistosome egg: development and secretions , 2001, Parasitology.

[27]  A. Sher,et al.  Fc epsilonRI-deficient mice infected with Schistosoma mansoni mount normal Th2-type responses while displaying enhanced liver pathology. , 1997, Journal of immunology.

[28]  Kenneth M. Murphy,et al.  Functional diversity of helper T lymphocytes , 1996, Nature.

[29]  A. Woodard,et al.  Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells , 1995, The Journal of experimental medicine.

[30]  K. Murphy,et al.  The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model , 1995, The Journal of experimental medicine.

[31]  M. Schlaak,et al.  Major allergen Phl p Vb in timothy grass is a novel pollen RNase , 1995, FEBS letters.

[32]  A. Loukas,et al.  Proteases in helminth- and allergen- induced inflammatory responses. , 2006, Chemical immunology and allergy.

[33]  M. Schlaak,et al.  The major birch pollen allergen, Bet v 1, shows ribonuclease activity , 2004, Planta.

[34]  J. Brouwers,et al.  A Novel Host-Parasite Lipid Cross-talk SCHISTOSOMAL LYSO-PHOSPHATIDYLSERINE ACTIVATES TOLL-LIKE RECEPTOR 2 AND AFFECTS IMMUNE POLARIZATION* , 2002 .

[35]  Jay K Kolls,et al.  The Biological Functions of T Helper 17 Cell Effector Cytokines in Inflammation , 2022 .