IFNγ and IL-12 restrict Th2 responses during Helminth/Plasmodium co-infection and promote IFNγ from Th2 cells

Stephanie M Coomes, Victoria S Pelly, Yashaswini Kannan, Isobel S Okoye, Stephanie Czieso, Lewis J Entwistle, Jimena Perez-Lloret, Nikolay Nikolov, Alexandre J Potocnik, Judit Biró, Jean Langhorne, Mark S Wilson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)e1004994
JournalPLoS Pathogens
Volume11
Issue number7
DOIs
Publication statusPublished - 6 Jul 2015

Keywords

  • adoptive transfer
  • animalslogy/metabolism Mice Plasmids/*genetics Promoter Regions (Genetics) Sheep
  • cell separation
  • coinfection/immunology
  • disease models
  • enzyme-linked immunosorbent assay
  • flow cytometry
  • interferon-gamma/immunology
  • Interleukin-12/immunology
  • lymphocyte activation/immunology
  • malaria/immunology
  • mice
  • nematospiroides dubius/immunology
  • Plasmodium chabaudi/immunology
  • polymerase chain reaction
  • strongylida infections/immunology
  • Th2 Cells/immunology

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