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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

Blockade of IL-12 and IFNγ prevents optimal IFNγ production by Th2 cells.A–C). In vitro Th2 (CD4+TCRβ+Il4gfp+) cells were transferred to Rag1–/–recipient mice for 14 days. Mice were infected with P. chabaudi and harvested at d8 post-infection. Mice were treated i.p. with 0.5mg anti-IL12 and anti-IFNγ at days -1, 6, 13, and 19. B). IFNγ production by transferred Th2 cells in the spleen, as determined by ICS. C). Il4gfp expression in transferred cells in the spleen. Data representative of 2 independent experiments with 5 mice per group. * denotes P<0.05.
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ppat.1004994.g008: Blockade of IL-12 and IFNγ prevents optimal IFNγ production by Th2 cells.A–C). In vitro Th2 (CD4+TCRβ+Il4gfp+) cells were transferred to Rag1–/–recipient mice for 14 days. Mice were infected with P. chabaudi and harvested at d8 post-infection. Mice were treated i.p. with 0.5mg anti-IL12 and anti-IFNγ at days -1, 6, 13, and 19. B). IFNγ production by transferred Th2 cells in the spleen, as determined by ICS. C). Il4gfp expression in transferred cells in the spleen. Data representative of 2 independent experiments with 5 mice per group. * denotes P<0.05.

Mentions: We next tested whether IFNγ, which contributes to Th1 differentiation [48], was required for IFNγ expression by Th2 cells. To do this, we blocked IFNγ, IL-12, or both IFNγ and IL-12 throughout the experiment (Fig 8A). Blockade of IFNγ or IL-12 alone did not have a major impact on IFNγ production by Th2 cells (Fig 8B). As above, IL-12 blockade preserved Il4gfp expression in a population of Th2 cells (Fig 8C). However, blockade of both IFNγ and IL-12 led to a >50% reduction in IFNγ-expressing cells deriving from Th2 cells (from 66.7%±1.5% IFNγ+ cells to 31.6%±3.4% IFNγ+ cells, Fig 8B), indicating that both IL-12 and IFNγ were required for optimal conversion of Th2 cells into IFNγ-secreting cells during Plasmodium infection. Despite a 50% reduction in IFNγ-secreting cells following IL-12 and IFNγ blockade, the remaining ~30% of IFNγ+ cells were sufficient to prevent high parasitemia (S5 Fig).


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)

Blockade of IL-12 and IFNγ prevents optimal IFNγ production by Th2 cells.A–C). In vitro Th2 (CD4+TCRβ+Il4gfp+) cells were transferred to Rag1–/–recipient mice for 14 days. Mice were infected with P. chabaudi and harvested at d8 post-infection. Mice were treated i.p. with 0.5mg anti-IL12 and anti-IFNγ at days -1, 6, 13, and 19. B). IFNγ production by transferred Th2 cells in the spleen, as determined by ICS. C). Il4gfp expression in transferred cells in the spleen. Data representative of 2 independent experiments with 5 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.g008: Blockade of IL-12 and IFNγ prevents optimal IFNγ production by Th2 cells.A–C). In vitro Th2 (CD4+TCRβ+Il4gfp+) cells were transferred to Rag1–/–recipient mice for 14 days. Mice were infected with P. chabaudi and harvested at d8 post-infection. Mice were treated i.p. with 0.5mg anti-IL12 and anti-IFNγ at days -1, 6, 13, and 19. B). IFNγ production by transferred Th2 cells in the spleen, as determined by ICS. C). Il4gfp expression in transferred cells in the spleen. Data representative of 2 independent experiments with 5 mice per group. * denotes P<0.05.
Mentions: We next tested whether IFNγ, which contributes to Th1 differentiation [48], was required for IFNγ expression by Th2 cells. To do this, we blocked IFNγ, IL-12, or both IFNγ and IL-12 throughout the experiment (Fig 8A). Blockade of IFNγ or IL-12 alone did not have a major impact on IFNγ production by Th2 cells (Fig 8B). As above, IL-12 blockade preserved Il4gfp expression in a population of Th2 cells (Fig 8C). However, blockade of both IFNγ and IL-12 led to a >50% reduction in IFNγ-expressing cells deriving from Th2 cells (from 66.7%±1.5% IFNγ+ cells to 31.6%±3.4% IFNγ+ cells, Fig 8B), indicating that both IL-12 and IFNγ were required for optimal conversion of Th2 cells into IFNγ-secreting cells during Plasmodium infection. Despite a 50% reduction in IFNγ-secreting cells following IL-12 and IFNγ blockade, the remaining ~30% of IFNγ+ cells were sufficient to prevent high parasitemia (S5 Fig).

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