title: Litomosoides sigmodontis induces TGF-β receptor responsive, IL-10-producing T cells that suppress bystander T-cell proliferation in mice.
abstract: Helminth parasites suppress immune responses to prolong their survival within the mammalian host. Thereby not only helminth-specific but also nonhelminth-specific bystander immune responses are suppressed. Here, we use the murine model of Litomosoides sigmodontis infection to elucidate the underlying mechanisms leading to this bystander T-cell suppression. When OT-II T cells specific for the third-party antigen ovalbumin are transferred into helminth-infected mice, these cells respond to antigen-specific stimulation with reduced proliferation compared to activation within non-infected mice. Thus, the presence of parasitic worms in the thoracic cavity translates to suppression of T cells with a different specificity at a different site. By eliminating regulatory receptors, cytokines, and cell populations from this system, we provide evidence for a two-staged process. Parasite products first engage the TGF-β receptor on host-derived T cells that are central to suppression. In a second step, host-derived T cells produce IL-10 and subsequently suppress the adoptively transferred OT-II T cells. Terminal suppression was IL-10-dependant but independent of intrinsic TGF-β receptor- or PD-1-mediated signaling in the suppressed OT-II T cells. Blockade of the same key suppression mediators, i.e. TGF-β- and IL-10 receptor, also ameliorated the suppression of IgG response to bystander antigen vaccination in L. sigmodontis-infected mice.
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Hartmann
authors.affiliation: University Hospital Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Minka
authors.initials: M
authors.lastname: Breloer
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D024201:Bystander Effect / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000469:parasitology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D005368:Filariasis / Q000235:genetics / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D005370:Filarioidea / Q000276:immunology; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000469:parasitology; D018418:Th2 Cells / Q000276:immunology* / Q000469:parasitology
chemical_list: C556062:IL10 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D018125:Receptors, Transforming Growth Factor beta; D016753:Interleukin-10; D010047:Ovalbumin
keywords: Filaria; Helminth; IL-10; Immune modulation; Mouse; Nematode; TGF-β; Treg cell