title: IFNγ and IL-12 Restrict Th2 Responses during Helminth/Plasmodium Co-Infection and Promote IFNγ from Th2 Cells.
abstract: Parasitic helminths establish chronic infections in mammalian hosts. Helminth/Plasmodium co-infections occur frequently in endemic areas. However, it is unclear whether Plasmodium infections compromise anti-helminth immunity, contributing to the chronicity of infection. Immunity to Plasmodium or helminths requires divergent CD4+ T cell-driven responses, dominated by IFNγ or IL-4, respectively. Recent literature has indicated that Th cells, including Th2 cells, have phenotypic plasticity with the ability to produce non-lineage associated cytokines. Whether such plasticity occurs during co-infection is unclear. In this study, we observed reduced anti-helminth Th2 cell responses and compromised anti-helminth immunity during Heligmosomoides polygyrus and Plasmodium chabaudi co-infection. Using newly established triple cytokine reporter mice (Il4gfpIfngyfpIl17aFP635), we demonstrated that Il4gfp+ Th2 cells purified from in vitro cultures or isolated ex vivo from helminth-infected mice up-regulated IFNγ following adoptive transfer into Rag1-/- mice infected with P. chabaudi. Functionally, Th2 cells that up-regulated IFNγ were transcriptionally re-wired and protected recipient mice from high parasitemia. Mechanistically, TCR stimulation and responsiveness to IL-12 and IFNγ, but not type I IFN, was required for optimal IFNγ production by Th2 cells. Finally, blockade of IL-12 and IFNγ during co-infection partially preserved anti-helminth Th2 responses. In summary, this study demonstrates that Th2 cells retain substantial plasticity with the ability to produce IFNγ during Plasmodium infection. Consequently, co-infection with Plasmodium spp. may contribute to the chronicity of helminth infection by reducing anti-helminth Th2 cells and converting them into IFNγ-secreting cells.
authors.affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Coomes
authors.affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Pelly
authors.affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.
authors.forename: Yashaswini
authors.initials: Y
authors.lastname: Kannan
authors.affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.
authors.forename: Isobel S
authors.initials: IS
authors.lastname: Okoye
authors.affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Czieso
authors.affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Entwistle
authors.affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.
authors.forename: Jimena
authors.initials: J
authors.lastname: Perez-Lloret
authors.affiliation: Division of Systems Biology, The Francis Crick Institute, London, United Kingdom.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Nikolov
authors.affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.
authors.forename: Alexandre J
authors.initials: AJ
authors.lastname: Potocnik
authors.affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.
authors.forename: Judit
authors.initials: J
authors.lastname: Biró
authors.affiliation: Division of Parasitology, Mill Hill Laboratories, London, United Kingdom.
authors.forename: Jean
authors.initials: J
authors.lastname: Langhorne
authors.affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wilson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002469:Cell Separation; D060085:Coinfection / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D018664:Interleukin-12 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008288:Malaria / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009351:Nematospiroides dubius / Q000276:immunology; D016788:Plasmodium chabaudi / Q000276:immunology; D016133:Polymerase Chain Reaction; D017206:Strongylida Infections / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D018664:Interleukin-12; D007371:Interferon-gamma