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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 on lymphopenia.A). Th2 cells generated from Il4gfp mice were polarized in vitro for 2 weeks, sorted as CD4+TCRβ+Il4gfp+, and 2.5x106 were transferred to OTII Rag1–/–recipient mice. Control groups received no T cells or sorted naïve T cells. 2 days post-transfer, mice were infected with 105P. chabaudi. B and C). Cytokine production in donor CD45.1+ or host cells in spleens, day 8 post-infection with P. Chabaudi, as determined by intracellular cytokine staining. D). IFNγ protein in serum, measured by ELISA. Data are representative of 2 independent experiments with 3–4 mice per group.
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ppat.1004994.g004: IFNγ production by Th2 cells does not depend on lymphopenia.A). Th2 cells generated from Il4gfp mice were polarized in vitro for 2 weeks, sorted as CD4+TCRβ+Il4gfp+, and 2.5x106 were transferred to OTII Rag1–/–recipient mice. Control groups received no T cells or sorted naïve T cells. 2 days post-transfer, mice were infected with 105P. chabaudi. B and C). Cytokine production in donor CD45.1+ or host cells in spleens, day 8 post-infection with P. Chabaudi, as determined by intracellular cytokine staining. D). IFNγ protein in serum, measured by ELISA. Data are representative of 2 independent experiments with 3–4 mice per group.

Mentions: When T cells undergo expansion in lymphopenic environments a population of rapidly dividing cells up-regulate CD44 and IFNγ [41–43]. To test whether conversion of Th2 cells into IFNγ-expressing cells could occur in a CD4+ T cell replete mouse, we transferred purified Th2 cells or naïve CD4+ T cells into OTII Rag1–/–mice [44], which have CD4+ T cells specific only for OVA peptide. We infected recipient mice with P. chabaudi and analyzed donor and host cells at day 8 post-infection (Fig 4A). Purified Th2 cells transferred into CD4+ OTII Rag1–/–mice, similar to Th2 cells transferred into Rag1–/–mice, produced IFNγ and down-regulated IL-4 (Fig 4B and 4C), contributing to elevated levels of serum IFNγ (Fig 4D). In contrast, host OVA-specific CD4+ T cells did not produce IFNγ following Plasmodium infection (Fig 4C). Thus, Th2 cell conversion was not dependent on lymphopenia.


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 on lymphopenia.A). Th2 cells generated from Il4gfp mice were polarized in vitro for 2 weeks, sorted as CD4+TCRβ+Il4gfp+, and 2.5x106 were transferred to OTII Rag1–/–recipient mice. Control groups received no T cells or sorted naïve T cells. 2 days post-transfer, mice were infected with 105P. chabaudi. B and C). Cytokine production in donor CD45.1+ or host cells in spleens, day 8 post-infection with P. Chabaudi, as determined by intracellular cytokine staining. D). IFNγ protein in serum, measured by ELISA. Data are representative of 2 independent experiments with 3–4 mice per group.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1004994.g004: IFNγ production by Th2 cells does not depend on lymphopenia.A). Th2 cells generated from Il4gfp mice were polarized in vitro for 2 weeks, sorted as CD4+TCRβ+Il4gfp+, and 2.5x106 were transferred to OTII Rag1–/–recipient mice. Control groups received no T cells or sorted naïve T cells. 2 days post-transfer, mice were infected with 105P. chabaudi. B and C). Cytokine production in donor CD45.1+ or host cells in spleens, day 8 post-infection with P. Chabaudi, as determined by intracellular cytokine staining. D). IFNγ protein in serum, measured by ELISA. Data are representative of 2 independent experiments with 3–4 mice per group.
Mentions: When T cells undergo expansion in lymphopenic environments a population of rapidly dividing cells up-regulate CD44 and IFNγ [41–43]. To test whether conversion of Th2 cells into IFNγ-expressing cells could occur in a CD4+ T cell replete mouse, we transferred purified Th2 cells or naïve CD4+ T cells into OTII Rag1–/–mice [44], which have CD4+ T cells specific only for OVA peptide. We infected recipient mice with P. chabaudi and analyzed donor and host cells at day 8 post-infection (Fig 4A). Purified Th2 cells transferred into CD4+ OTII Rag1–/–mice, similar to Th2 cells transferred into Rag1–/–mice, produced IFNγ and down-regulated IL-4 (Fig 4B and 4C), contributing to elevated levels of serum IFNγ (Fig 4D). In contrast, host OVA-specific CD4+ T cells did not produce IFNγ following Plasmodium infection (Fig 4C). Thus, Th2 cell conversion was not dependent on lymphopenia.

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