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IFNγ and IL-12 Restrict Th2 Responses during Helminth/Plasmodium Co-Infection and Promote IFNγ from Th2 Cells.

Coomes SM, Pelly VS, Kannan Y, Okoye IS, Czieso S, Entwistle LJ, Perez-Lloret J, Nikolov N, Potocnik AJ, Biró J, Langhorne J, Wilson MS - PLoS Pathog. (2015)

Bottom Line: Recent literature has indicated that Th cells, including Th2 cells, have phenotypic plasticity with the ability to produce non-lineage associated cytokines.Mechanistically, TCR stimulation and responsiveness to IL-12 and IFNγ, but not type I IFN, was required for optimal IFNγ production by Th2 cells.In summary, this study demonstrates that Th2 cells retain substantial plasticity with the ability to produce IFNγ during Plasmodium infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus

H. polygyrus-induced Th2 cells retain capacity to produce IFNγ during co-infection.A)–B). CD4+TCRβ+Il4gfp+Ifngyfp-Il17aFP635-ex vivo Th2 cells from d14 H. polygyrus-infected mice or naïve CD4+ T cells were transferred to d14 H. polygyrus-infected Rag1–/–recipient mice. Mice were infected with P. chabaudi and analyzed at day 8 post-infection. B). Cytokine reporter expression in transferred cells from spleens and mesenteric lymph nodes of recipient mice. Data representative of 2 separate experiments, with 4 mice per group. C). Ex vivo Th2 or naïve cells were transferred to recipient Rag1-/- mice, as in 9A. At day 8 post-infection with P. chabaudi, 2x105 mesenteric lymph nodes cells were stimulated with 10 μg/mL H. polygyrus antigen and 10 ng/mL IL-4. ELISAs were performed on cell supernatants after 5 days. Data are representative of 2 separate experiments. Lymph nodes were pooled from 2 recipient mice per group. Error bars represent technical replicates. D). Ex vivo Th2 or naïve cells were transferred to recipient Rag1-/- mice, as in 9A. At day 8 post-infection with P. chabaudi, CD4+TCRβ+Ifngyfp+Il4gfp-Il17aFP635- cells were sorted from pooled spleens of 2 recipient mice per group (following the sorting strategy as in Fig 2G). 9.6x104 purified converted CD4+TCRβ+Ifngyfp+Il4gfp-Il17aFP635- cells from a naïve or Th2 past were then cultured with 4x105 irradiated CD4+–depleted splenocytes and one of the following: 3x106 red blood cells from a P. chabaudi-infected donor mouse (day 8 post-infection) or 10 μg/mL H. polygyrus antigen. ELISAs were performed on cell supernatants after 5 days. Error bars represent technical replicates. Data are representative of 2 independent experiments.
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ppat.1004994.g009: H. polygyrus-induced Th2 cells retain capacity to produce IFNγ during co-infection.A)–B). CD4+TCRβ+Il4gfp+Ifngyfp-Il17aFP635-ex vivo Th2 cells from d14 H. polygyrus-infected mice or naïve CD4+ T cells were transferred to d14 H. polygyrus-infected Rag1–/–recipient mice. Mice were infected with P. chabaudi and analyzed at day 8 post-infection. B). Cytokine reporter expression in transferred cells from spleens and mesenteric lymph nodes of recipient mice. Data representative of 2 separate experiments, with 4 mice per group. C). Ex vivo Th2 or naïve cells were transferred to recipient Rag1-/- mice, as in 9A. At day 8 post-infection with P. chabaudi, 2x105 mesenteric lymph nodes cells were stimulated with 10 μg/mL H. polygyrus antigen and 10 ng/mL IL-4. ELISAs were performed on cell supernatants after 5 days. Data are representative of 2 separate experiments. Lymph nodes were pooled from 2 recipient mice per group. Error bars represent technical replicates. D). Ex vivo Th2 or naïve cells were transferred to recipient Rag1-/- mice, as in 9A. At day 8 post-infection with P. chabaudi, CD4+TCRβ+Ifngyfp+Il4gfp-Il17aFP635- cells were sorted from pooled spleens of 2 recipient mice per group (following the sorting strategy as in Fig 2G). 9.6x104 purified converted CD4+TCRβ+Ifngyfp+Il4gfp-Il17aFP635- cells from a naïve or Th2 past were then cultured with 4x105 irradiated CD4+–depleted splenocytes and one of the following: 3x106 red blood cells from a P. chabaudi-infected donor mouse (day 8 post-infection) or 10 μg/mL H. polygyrus antigen. ELISAs were performed on cell supernatants after 5 days. Error bars represent technical replicates. Data are representative of 2 independent experiments.

Mentions: Finally, we translated these new observations back into a co-infection scenario, as presented in Fig 1, and tested whether helminth-induced Th2 cells had the capacity to up-regulate IFNγ in a co-infection scenario. First, we purified ex vivo Il4gfp+Ifngyfp–Il17aFP635– Th2 cells from d14 H. polygyrus-infected mice and transferred them into day 14 H. polygyrus-infected Rag1–/–mice. Recipient mice were then co-infected with P. chabaudi and the transferred cells were analyzed at day 8 post P. chabaudi infection (Fig 9A). Similar to in vitro-derived Th2 cells, H. polygyrus-derived Th2 cells down-regulated Il4gfp and up-regulated Ifngyfp, albeit to a slightly lesser extent than naïve T cells (Fig 9B).


IFNγ and IL-12 Restrict Th2 Responses during Helminth/Plasmodium Co-Infection and Promote IFNγ from Th2 Cells.

Coomes SM, Pelly VS, Kannan Y, Okoye IS, Czieso S, Entwistle LJ, Perez-Lloret J, Nikolov N, Potocnik AJ, Biró J, Langhorne J, Wilson MS - PLoS Pathog. (2015)

H. polygyrus-induced Th2 cells retain capacity to produce IFNγ during co-infection.A)–B). CD4+TCRβ+Il4gfp+Ifngyfp-Il17aFP635-ex vivo Th2 cells from d14 H. polygyrus-infected mice or naïve CD4+ T cells were transferred to d14 H. polygyrus-infected Rag1–/–recipient mice. Mice were infected with P. chabaudi and analyzed at day 8 post-infection. B). Cytokine reporter expression in transferred cells from spleens and mesenteric lymph nodes of recipient mice. Data representative of 2 separate experiments, with 4 mice per group. C). Ex vivo Th2 or naïve cells were transferred to recipient Rag1-/- mice, as in 9A. At day 8 post-infection with P. chabaudi, 2x105 mesenteric lymph nodes cells were stimulated with 10 μg/mL H. polygyrus antigen and 10 ng/mL IL-4. ELISAs were performed on cell supernatants after 5 days. Data are representative of 2 separate experiments. Lymph nodes were pooled from 2 recipient mice per group. Error bars represent technical replicates. D). Ex vivo Th2 or naïve cells were transferred to recipient Rag1-/- mice, as in 9A. At day 8 post-infection with P. chabaudi, CD4+TCRβ+Ifngyfp+Il4gfp-Il17aFP635- cells were sorted from pooled spleens of 2 recipient mice per group (following the sorting strategy as in Fig 2G). 9.6x104 purified converted CD4+TCRβ+Ifngyfp+Il4gfp-Il17aFP635- cells from a naïve or Th2 past were then cultured with 4x105 irradiated CD4+–depleted splenocytes and one of the following: 3x106 red blood cells from a P. chabaudi-infected donor mouse (day 8 post-infection) or 10 μg/mL H. polygyrus antigen. ELISAs were performed on cell supernatants after 5 days. Error bars represent technical replicates. Data are representative of 2 independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4493106&req=5

ppat.1004994.g009: H. polygyrus-induced Th2 cells retain capacity to produce IFNγ during co-infection.A)–B). CD4+TCRβ+Il4gfp+Ifngyfp-Il17aFP635-ex vivo Th2 cells from d14 H. polygyrus-infected mice or naïve CD4+ T cells were transferred to d14 H. polygyrus-infected Rag1–/–recipient mice. Mice were infected with P. chabaudi and analyzed at day 8 post-infection. B). Cytokine reporter expression in transferred cells from spleens and mesenteric lymph nodes of recipient mice. Data representative of 2 separate experiments, with 4 mice per group. C). Ex vivo Th2 or naïve cells were transferred to recipient Rag1-/- mice, as in 9A. At day 8 post-infection with P. chabaudi, 2x105 mesenteric lymph nodes cells were stimulated with 10 μg/mL H. polygyrus antigen and 10 ng/mL IL-4. ELISAs were performed on cell supernatants after 5 days. Data are representative of 2 separate experiments. Lymph nodes were pooled from 2 recipient mice per group. Error bars represent technical replicates. D). Ex vivo Th2 or naïve cells were transferred to recipient Rag1-/- mice, as in 9A. At day 8 post-infection with P. chabaudi, CD4+TCRβ+Ifngyfp+Il4gfp-Il17aFP635- cells were sorted from pooled spleens of 2 recipient mice per group (following the sorting strategy as in Fig 2G). 9.6x104 purified converted CD4+TCRβ+Ifngyfp+Il4gfp-Il17aFP635- cells from a naïve or Th2 past were then cultured with 4x105 irradiated CD4+–depleted splenocytes and one of the following: 3x106 red blood cells from a P. chabaudi-infected donor mouse (day 8 post-infection) or 10 μg/mL H. polygyrus antigen. ELISAs were performed on cell supernatants after 5 days. Error bars represent technical replicates. Data are representative of 2 independent experiments.
Mentions: Finally, we translated these new observations back into a co-infection scenario, as presented in Fig 1, and tested whether helminth-induced Th2 cells had the capacity to up-regulate IFNγ in a co-infection scenario. First, we purified ex vivo Il4gfp+Ifngyfp–Il17aFP635– Th2 cells from d14 H. polygyrus-infected mice and transferred them into day 14 H. polygyrus-infected Rag1–/–mice. Recipient mice were then co-infected with P. chabaudi and the transferred cells were analyzed at day 8 post P. chabaudi infection (Fig 9A). Similar to in vitro-derived Th2 cells, H. polygyrus-derived Th2 cells down-regulated Il4gfp and up-regulated Ifngyfp, albeit to a slightly lesser extent than naïve T cells (Fig 9B).

Bottom Line: Recent literature has indicated that Th cells, including Th2 cells, have phenotypic plasticity with the ability to produce non-lineage associated cytokines.Mechanistically, TCR stimulation and responsiveness to IL-12 and IFNγ, but not type I IFN, was required for optimal IFNγ production by Th2 cells.In summary, this study demonstrates that Th2 cells retain substantial plasticity with the ability to produce IFNγ during Plasmodium infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus