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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/ P. chabaudi co-infection leads to impaired Th2 responses.A-C). Triple reporter mice were orally infected with 200 H. polygyrus larvae. 6 days post-infection, mice were infected i.p. with 105P. chabaudi. At day 8 of P. chabaudi infection (d14 H. polygyrus), mice were harvested. B). Total numbers of CD4+CD44hiIl4gfp+ cells in the mesenteric lymph nodes. Data are representative of 5 independent experiments with 2–4 mice per group. C). IgE measured in the serum by ELISA from 3 pooled experiments. D and E). C57BL/6 mice were infected with 200 H. polygyrus larvae, treated on 2 consecutive days (days 14–15) with pyrantel pamoate (5 mg), infected with 105P. chabaudi, and re-infected with H. polygyrus. Adult worms in intestine were counted on day 51. Data are representative of 4 independent experiments with 6–7 mice per group. * denotes P<0.05.
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ppat.1004994.g001: H. polygyrus/ P. chabaudi co-infection leads to impaired Th2 responses.A-C). Triple reporter mice were orally infected with 200 H. polygyrus larvae. 6 days post-infection, mice were infected i.p. with 105P. chabaudi. At day 8 of P. chabaudi infection (d14 H. polygyrus), mice were harvested. B). Total numbers of CD4+CD44hiIl4gfp+ cells in the mesenteric lymph nodes. Data are representative of 5 independent experiments with 2–4 mice per group. C). IgE measured in the serum by ELISA from 3 pooled experiments. D and E). C57BL/6 mice were infected with 200 H. polygyrus larvae, treated on 2 consecutive days (days 14–15) with pyrantel pamoate (5 mg), infected with 105P. chabaudi, and re-infected with H. polygyrus. Adult worms in intestine were counted on day 51. Data are representative of 4 independent experiments with 6–7 mice per group. * denotes P<0.05.

Mentions: To assess the impact of concomitant Plasmodium infection on the development of Th2 responses, we infected mice with H. polygyrus and 6 days later with 105P. chabaudi-infected red blood cells (Fig 1A). To accurately identify simultaneous transcription of Th1 (Ifng), Th2 (Il4) and Th17 (Il17a) lineage-defining genes, we generated a triple cytokine reporter mouse (Il4gfpIfngyfpIl17aCreR26FP635) using existing and new fluorescent cytokine reporter mouse strains [35–37] (S1 Fig). Following infection with L3 larvae of the intestinal helminth, H. polygyrus, we observed a significant expansion of Il4gfp+ CD4+ Th2 cells in the mesenteric lymph nodes 14 days post-infection. Co-infected mice had significantly reduced numbers of Il4gfp+ CD4+ Th2 cells in the mesenteric lymph nodes (Fig 1B) as well as a reduction in serum IgE (Fig 1C) and decreased expression of the alternative macrophage activation marker, Retnla (Relmα) in the gut (S2 Fig). These data indicated that helminth-elicited Th2 cells and Th2-driven immune responses were compromised during Plasmodium co-infection. The reduced Il4gfp+ cells in the mesenteric lymph nodes correlated with an increase in Ifngyfp+ cells in the spleen 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)

H. polygyrus/ P. chabaudi co-infection leads to impaired Th2 responses.A-C). Triple reporter mice were orally infected with 200 H. polygyrus larvae. 6 days post-infection, mice were infected i.p. with 105P. chabaudi. At day 8 of P. chabaudi infection (d14 H. polygyrus), mice were harvested. B). Total numbers of CD4+CD44hiIl4gfp+ cells in the mesenteric lymph nodes. Data are representative of 5 independent experiments with 2–4 mice per group. C). IgE measured in the serum by ELISA from 3 pooled experiments. D and E). C57BL/6 mice were infected with 200 H. polygyrus larvae, treated on 2 consecutive days (days 14–15) with pyrantel pamoate (5 mg), infected with 105P. chabaudi, and re-infected with H. polygyrus. Adult worms in intestine were counted on day 51. Data are representative of 4 independent experiments with 6–7 mice per group. * denotes P<0.05.
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ppat.1004994.g001: H. polygyrus/ P. chabaudi co-infection leads to impaired Th2 responses.A-C). Triple reporter mice were orally infected with 200 H. polygyrus larvae. 6 days post-infection, mice were infected i.p. with 105P. chabaudi. At day 8 of P. chabaudi infection (d14 H. polygyrus), mice were harvested. B). Total numbers of CD4+CD44hiIl4gfp+ cells in the mesenteric lymph nodes. Data are representative of 5 independent experiments with 2–4 mice per group. C). IgE measured in the serum by ELISA from 3 pooled experiments. D and E). C57BL/6 mice were infected with 200 H. polygyrus larvae, treated on 2 consecutive days (days 14–15) with pyrantel pamoate (5 mg), infected with 105P. chabaudi, and re-infected with H. polygyrus. Adult worms in intestine were counted on day 51. Data are representative of 4 independent experiments with 6–7 mice per group. * denotes P<0.05.
Mentions: To assess the impact of concomitant Plasmodium infection on the development of Th2 responses, we infected mice with H. polygyrus and 6 days later with 105P. chabaudi-infected red blood cells (Fig 1A). To accurately identify simultaneous transcription of Th1 (Ifng), Th2 (Il4) and Th17 (Il17a) lineage-defining genes, we generated a triple cytokine reporter mouse (Il4gfpIfngyfpIl17aCreR26FP635) using existing and new fluorescent cytokine reporter mouse strains [35–37] (S1 Fig). Following infection with L3 larvae of the intestinal helminth, H. polygyrus, we observed a significant expansion of Il4gfp+ CD4+ Th2 cells in the mesenteric lymph nodes 14 days post-infection. Co-infected mice had significantly reduced numbers of Il4gfp+ CD4+ Th2 cells in the mesenteric lymph nodes (Fig 1B) as well as a reduction in serum IgE (Fig 1C) and decreased expression of the alternative macrophage activation marker, Retnla (Relmα) in the gut (S2 Fig). These data indicated that helminth-elicited Th2 cells and Th2-driven immune responses were compromised during Plasmodium co-infection. The reduced Il4gfp+ cells in the mesenteric lymph nodes correlated with an increase in Ifngyfp+ cells in the spleen 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