journal.ppat.1004994.PDF (2.49 MB)
IFNγ and IL-12 restrict Th2 responses during helminth/Plasmodium co-infection and promote IFNγ from Th2 cells
journal contributionposted on 2020-07-15, 13:06 authored by 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
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.
Adoptive TransferAnimalsCell SeparationCoinfectionDisease Models, AnimalEnzyme-Linked Immunosorbent AssayFlow CytometryInterferon-gammaInterleukin-12Lymphocyte ActivationMalariaMiceMice, KnockoutNematospiroides dubiusPlasmodium chabaudiPolymerase Chain ReactionStrongylida InfectionsTh2 CellsLanghorne U117584248Wilson, M MC_UP_A253_1028FC-ackAS-ackBRF-ackVirology0605 Microbiology1107 Immunology1108 Medical Microbiology