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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 during co-infection preserves Th2 responses.A-C). C57BL/6 mice were orally infected with 200 H. polygyrus larvae. 6 days post-infection, mice were infected with 105P. chabaudi. At day 8-post infection with P. chabaudi (d14 H. polygyrus), mice were harvested. Mice were treated with 0.5 mg of anti-IL-12 and anti-IFNγ i.p. at days 0, 5, and 11. B). Total numbers of CD4+CD44hiIl4gfp+ cells in the mesenteric lymph nodes. C). IgE measured in the serum by ELISA. Data are representative of 2 independent experiments with 6 mice per group. * denotes P<0.05.
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ppat.1004994.g010: Blockade of IL-12 and IFNγ during co-infection preserves Th2 responses.A-C). C57BL/6 mice were orally infected with 200 H. polygyrus larvae. 6 days post-infection, mice were infected with 105P. chabaudi. At day 8-post infection with P. chabaudi (d14 H. polygyrus), mice were harvested. Mice were treated with 0.5 mg of anti-IL-12 and anti-IFNγ i.p. at days 0, 5, and 11. B). Total numbers of CD4+CD44hiIl4gfp+ cells in the mesenteric lymph nodes. C). IgE measured in the serum by ELISA. Data are representative of 2 independent experiments with 6 mice per group. * denotes P<0.05.

Mentions: Finally, we tested whether the factors promoting IFNγ in the adoptive transfer model, IL-12 and IFNγ (Fig 8B), were responsible for the loss of Th2 cells and type-2 immunity during H. polygyrus and P. chabaudi co-infection. To do this, we infected wild type mice with H. polygyrus and at six days post-infection, mice were co-infected with P. chabaudi with or without blocking antibodies to IL-12 and IFNγ (Fig 10A). Blockade of IL-12 and IFNγ preserved Il4gfp+ Th2 cells in co-infected mice (Fig 10B) and maintained elevated levels of helminth-induced type-2-associated IgE (Fig 10C). However, despite preserving Th2 cells and IgE, proficient anti-helminth immunity was not fully restored in mice given blocking antibodies (S6 Fig). Thus, IL-12 and IFNγ play a major role compromising Th2 responses during helminth/ Plasmodium co-infection, but additional factors also contribute to compromised anti-helminth immunity during co-infection.


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 during co-infection preserves Th2 responses.A-C). C57BL/6 mice were orally infected with 200 H. polygyrus larvae. 6 days post-infection, mice were infected with 105P. chabaudi. At day 8-post infection with P. chabaudi (d14 H. polygyrus), mice were harvested. Mice were treated with 0.5 mg of anti-IL-12 and anti-IFNγ i.p. at days 0, 5, and 11. B). Total numbers of CD4+CD44hiIl4gfp+ cells in the mesenteric lymph nodes. C). IgE measured in the serum by ELISA. Data are representative of 2 independent experiments with 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.g010: Blockade of IL-12 and IFNγ during co-infection preserves Th2 responses.A-C). C57BL/6 mice were orally infected with 200 H. polygyrus larvae. 6 days post-infection, mice were infected with 105P. chabaudi. At day 8-post infection with P. chabaudi (d14 H. polygyrus), mice were harvested. Mice were treated with 0.5 mg of anti-IL-12 and anti-IFNγ i.p. at days 0, 5, and 11. B). Total numbers of CD4+CD44hiIl4gfp+ cells in the mesenteric lymph nodes. C). IgE measured in the serum by ELISA. Data are representative of 2 independent experiments with 6 mice per group. * denotes P<0.05.
Mentions: Finally, we tested whether the factors promoting IFNγ in the adoptive transfer model, IL-12 and IFNγ (Fig 8B), were responsible for the loss of Th2 cells and type-2 immunity during H. polygyrus and P. chabaudi co-infection. To do this, we infected wild type mice with H. polygyrus and at six days post-infection, mice were co-infected with P. chabaudi with or without blocking antibodies to IL-12 and IFNγ (Fig 10A). Blockade of IL-12 and IFNγ preserved Il4gfp+ Th2 cells in co-infected mice (Fig 10B) and maintained elevated levels of helminth-induced type-2-associated IgE (Fig 10C). However, despite preserving Th2 cells and IgE, proficient anti-helminth immunity was not fully restored in mice given blocking antibodies (S6 Fig). Thus, IL-12 and IFNγ play a major role compromising Th2 responses during helminth/ Plasmodium co-infection, but additional factors also contribute to compromised anti-helminth immunity during co-infection.

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