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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

IFNγ production by Th2 cells does not depend of type I IFN.A). CD4+TCRβ+Il4gfp+Ifnar+/+ or Ifnar–/–Th2 cells were transferred to Rag1–/–mice. Recipient mice were infected with 105P. chabaudi 14 days later and mice were harvested at day 8 post-infection. B and C). Cytokine expression in transferred cells in the spleen (ICS). D). IFNγ protein in serum, measured by ELISA. E). Percent parasitemia, determined by blinded counting of Giemsa-stained blood smears. F). Hemoglobin and red blood cell counts determined by Vetscan. Data are representative of 2 independent experiments with 5–6 mice per group. * denotes P<0.05.
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ppat.1004994.g006: IFNγ production by Th2 cells does not depend of type I IFN.A). CD4+TCRβ+Il4gfp+Ifnar+/+ or Ifnar–/–Th2 cells were transferred to Rag1–/–mice. Recipient mice were infected with 105P. chabaudi 14 days later and mice were harvested at day 8 post-infection. B and C). Cytokine expression in transferred cells in the spleen (ICS). D). IFNγ protein in serum, measured by ELISA. E). Percent parasitemia, determined by blinded counting of Giemsa-stained blood smears. F). Hemoglobin and red blood cell counts determined by Vetscan. Data are representative of 2 independent experiments with 5–6 mice per group. * denotes P<0.05.

Mentions: It has been shown previously that type I IFN signaling was required for IFNγ production from LCMV-specific TCR transgenic Th2 cells [34]. We had also observed that type 1 IFN was a candidate cytokine that could contribute to the transcriptional profile of converted Th2 cells (Fig 3E). We therefore tested the requirement for type 1 IFN signaling by crossing Ifnar–/–mice with Il4gfp reporter mice. FACS purified Il4gfp+Ifnar–/–or Il4gfp+Ifnar+/+ Th2 cells were transferred to Rag1–/–recipient mice, subsequently infected with P. chabaudi and analyzed at day 8 post-infection (Fig 6A). Both type I IFN responsive and unresponsive Th2 cells were capable of up-regulating IFNγ (Fig 6B and 6C), contributing to serum IFNγ levels (Fig 6D). Furthermore, type I IFN responsive and unresponsive Th2 cells afforded similar protection from high parasitemia (Fig 6E), and prevented a loss in hemoglobin and red blood cells (Fig 6F). Thus, type I IFN signaling was dispensable for IFNγ production from ex-Th2 cells and for controlling high parasitemia.


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)

IFNγ production by Th2 cells does not depend of type I IFN.A). CD4+TCRβ+Il4gfp+Ifnar+/+ or Ifnar–/–Th2 cells were transferred to Rag1–/–mice. Recipient mice were infected with 105P. chabaudi 14 days later and mice were harvested at day 8 post-infection. B and C). Cytokine expression in transferred cells in the spleen (ICS). D). IFNγ protein in serum, measured by ELISA. E). Percent parasitemia, determined by blinded counting of Giemsa-stained blood smears. F). Hemoglobin and red blood cell counts determined by Vetscan. Data are representative of 2 independent experiments with 5–6 mice per group. * denotes P<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1004994.g006: IFNγ production by Th2 cells does not depend of type I IFN.A). CD4+TCRβ+Il4gfp+Ifnar+/+ or Ifnar–/–Th2 cells were transferred to Rag1–/–mice. Recipient mice were infected with 105P. chabaudi 14 days later and mice were harvested at day 8 post-infection. B and C). Cytokine expression in transferred cells in the spleen (ICS). D). IFNγ protein in serum, measured by ELISA. E). Percent parasitemia, determined by blinded counting of Giemsa-stained blood smears. F). Hemoglobin and red blood cell counts determined by Vetscan. Data are representative of 2 independent experiments with 5–6 mice per group. * denotes P<0.05.
Mentions: It has been shown previously that type I IFN signaling was required for IFNγ production from LCMV-specific TCR transgenic Th2 cells [34]. We had also observed that type 1 IFN was a candidate cytokine that could contribute to the transcriptional profile of converted Th2 cells (Fig 3E). We therefore tested the requirement for type 1 IFN signaling by crossing Ifnar–/–mice with Il4gfp reporter mice. FACS purified Il4gfp+Ifnar–/–or Il4gfp+Ifnar+/+ Th2 cells were transferred to Rag1–/–recipient mice, subsequently infected with P. chabaudi and analyzed at day 8 post-infection (Fig 6A). Both type I IFN responsive and unresponsive Th2 cells were capable of up-regulating IFNγ (Fig 6B and 6C), contributing to serum IFNγ levels (Fig 6D). Furthermore, type I IFN responsive and unresponsive Th2 cells afforded similar protection from high parasitemia (Fig 6E), and prevented a loss in hemoglobin and red blood cells (Fig 6F). Thus, type I IFN signaling was dispensable for IFNγ production from ex-Th2 cells and for controlling high parasitemia.

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