TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus

Yashaswini Kannan, Lewis J. Entwistle, Victoria S. Pelly, Jimena Perez-Lloret, Alan W. Walker, Steven C. Ley, Mark S. Wilson

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Abstract

TPL-2 (COT, MAP3K8) kinase activates the MEK1/2-ERK1/2 MAPK signaling pathway in innate immune responses following TLR, TNFR1 and IL-1R stimulation. TPL-2 contributes to type-1/Th17-mediated autoimmunity and control of intracellular pathogens. We recently demonstrated TPL-2 reduces severe airway allergy to house dust mite by negatively regulating type-2 responses. In the present study, we found that TPL-2 deficiency resulted in resistance to Heligmosomoides polygyrus infection, with accelerated worm expulsion, reduced fecal egg burden and reduced worm fitness. Using co-housing experiments, we found resistance to infection in TPL-2 deficient mice (Map3k8–/–) was independent of microbiota alterations in H. polygyrus infected WT and Map3k8–/–mice. Additionally, our data demonstrated immunity to H. polygyrus infection in TPL-2 deficient mice was not due to dysregulated type-2 immune responses. Genome-wide analysis of intestinal tissue from infected TPL-2-deficient mice identified elevated expression of genes involved in chemotaxis and homing of leukocytes and cells, including Ccl24 and alternatively activated genes. Indeed, Map3k8–/–mice had a significant influx of eosinophils, neutrophils, monocytes and Il4GFP+ T cells. Conditional knockout experiments demonstrated that specific deletion of TPL-2 in CD11c+ cells, but not Villin+ epithelial cells, LysM+ myeloid cells or CD4+ T cells, led to accelerated resistance to H. polygyrus. In line with a central role of CD11c+ cells, CD11c+ CD11b+ cells isolated from TPL-2-deficient mice had elevated Ccl24. Finally, Ccl24 neutralization in TPL-2 deficient mice significantly decreased the expression of Arg1, Retnla, Chil3 and Ear11 correlating with a loss of resistance to H. polygyrus. These observations suggest that TPL-2-regulated Ccl24 in CD11c+CD11b+ cells prevents accelerated type-2 mediated immunity to H. polygyrus. Collectively, this study identifies a previously unappreciated role for TPL-2 controlling immune responses to H. polygyrus infection by restricting Ccl24 production.
Original languageEnglish
Article numbere1006536
Number of pages21
JournalPLoS Pathogens
Volume13
Issue number7
DOIs
Publication statusPublished - 31 Jul 2017

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Nematospiroides dubius
Immunity
Infection
Leukocyte Chemotaxis
Receptors, Tumor Necrosis Factor, Type I
T-Lymphocytes
Pyroglyphidae
Microbiota
Myeloid Cells
Autoimmunity
Eosinophils
Innate Immunity
Ovum
Monocytes
Hypersensitivity
Neutrophils
Phosphotransferases
Epithelial Cells
Genome
Gene Expression

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Kannan, Y., Entwistle, L. J., Pelly, V. S., Perez-Lloret, J., Walker, A. W., Ley, S. C., & Wilson, M. S. (2017). TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus. PLoS Pathogens, 13(7), [e1006536]. https://doi.org/10.1371/journal.ppat.1006536

TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus. / Kannan, Yashaswini; Entwistle, Lewis J.; Pelly, Victoria S.; Perez-Lloret, Jimena; Walker, Alan W.; Ley, Steven C.; Wilson, Mark S.

In: PLoS Pathogens, Vol. 13, No. 7, e1006536, 31.07.2017.

Research output: Contribution to journalArticle

Kannan, Y, Entwistle, LJ, Pelly, VS, Perez-Lloret, J, Walker, AW, Ley, SC & Wilson, MS 2017, 'TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus', PLoS Pathogens, vol. 13, no. 7, e1006536. https://doi.org/10.1371/journal.ppat.1006536
Kannan Y, Entwistle LJ, Pelly VS, Perez-Lloret J, Walker AW, Ley SC et al. TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus. PLoS Pathogens. 2017 Jul 31;13(7). e1006536. https://doi.org/10.1371/journal.ppat.1006536
Kannan, Yashaswini ; Entwistle, Lewis J. ; Pelly, Victoria S. ; Perez-Lloret, Jimena ; Walker, Alan W. ; Ley, Steven C. ; Wilson, Mark S. / TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus. In: PLoS Pathogens. 2017 ; Vol. 13, No. 7.
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abstract = "TPL-2 (COT, MAP3K8) kinase activates the MEK1/2-ERK1/2 MAPK signaling pathway in innate immune responses following TLR, TNFR1 and IL-1R stimulation. TPL-2 contributes to type-1/Th17-mediated autoimmunity and control of intracellular pathogens. We recently demonstrated TPL-2 reduces severe airway allergy to house dust mite by negatively regulating type-2 responses. In the present study, we found that TPL-2 deficiency resulted in resistance to Heligmosomoides polygyrus infection, with accelerated worm expulsion, reduced fecal egg burden and reduced worm fitness. Using co-housing experiments, we found resistance to infection in TPL-2 deficient mice (Map3k8–/–) was independent of microbiota alterations in H. polygyrus infected WT and Map3k8–/–mice. Additionally, our data demonstrated immunity to H. polygyrus infection in TPL-2 deficient mice was not due to dysregulated type-2 immune responses. Genome-wide analysis of intestinal tissue from infected TPL-2-deficient mice identified elevated expression of genes involved in chemotaxis and homing of leukocytes and cells, including Ccl24 and alternatively activated genes. Indeed, Map3k8–/–mice had a significant influx of eosinophils, neutrophils, monocytes and Il4GFP+ T cells. Conditional knockout experiments demonstrated that specific deletion of TPL-2 in CD11c+ cells, but not Villin+ epithelial cells, LysM+ myeloid cells or CD4+ T cells, led to accelerated resistance to H. polygyrus. In line with a central role of CD11c+ cells, CD11c+ CD11b+ cells isolated from TPL-2-deficient mice had elevated Ccl24. Finally, Ccl24 neutralization in TPL-2 deficient mice significantly decreased the expression of Arg1, Retnla, Chil3 and Ear11 correlating with a loss of resistance to H. polygyrus. These observations suggest that TPL-2-regulated Ccl24 in CD11c+CD11b+ cells prevents accelerated type-2 mediated immunity to H. polygyrus. Collectively, this study identifies a previously unappreciated role for TPL-2 controlling immune responses to H. polygyrus infection by restricting Ccl24 production.",
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AU - Kannan, Yashaswini

AU - Entwistle, Lewis J.

AU - Pelly, Victoria S.

AU - Perez-Lloret, Jimena

AU - Walker, Alan W.

AU - Ley, Steven C.

AU - Wilson, Mark S.

N1 - Funding: This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001220), the UK Medical Research Council (FC001220), and the Wellcome Trust (FC001200). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We are indebted to The Francis Crick Institute Flow Cytometry facility, and in particular Bhavik Patel, Graham Preece, Wayne Turnbull and Phil Hobson. We would also like to thank The Francis Crick Institute Procedural Service Section for production of GA lines and Biological Services, especially Trisha Norton, Keith Williams and Adebambo Adekoya for animal husbandry and technical support; to Riccardo Guidi for constructive discussions and technical assistance. We would like to thank Gitta Stockinger and AhR Immunity Laboratory for providing technical support and reagents throughout this study. We also thank Richard Rance and the Wellcome Trust Sanger Institute’s 454 pyrosequencing team for generating 16S rRNA gene data.

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N2 - TPL-2 (COT, MAP3K8) kinase activates the MEK1/2-ERK1/2 MAPK signaling pathway in innate immune responses following TLR, TNFR1 and IL-1R stimulation. TPL-2 contributes to type-1/Th17-mediated autoimmunity and control of intracellular pathogens. We recently demonstrated TPL-2 reduces severe airway allergy to house dust mite by negatively regulating type-2 responses. In the present study, we found that TPL-2 deficiency resulted in resistance to Heligmosomoides polygyrus infection, with accelerated worm expulsion, reduced fecal egg burden and reduced worm fitness. Using co-housing experiments, we found resistance to infection in TPL-2 deficient mice (Map3k8–/–) was independent of microbiota alterations in H. polygyrus infected WT and Map3k8–/–mice. Additionally, our data demonstrated immunity to H. polygyrus infection in TPL-2 deficient mice was not due to dysregulated type-2 immune responses. Genome-wide analysis of intestinal tissue from infected TPL-2-deficient mice identified elevated expression of genes involved in chemotaxis and homing of leukocytes and cells, including Ccl24 and alternatively activated genes. Indeed, Map3k8–/–mice had a significant influx of eosinophils, neutrophils, monocytes and Il4GFP+ T cells. Conditional knockout experiments demonstrated that specific deletion of TPL-2 in CD11c+ cells, but not Villin+ epithelial cells, LysM+ myeloid cells or CD4+ T cells, led to accelerated resistance to H. polygyrus. In line with a central role of CD11c+ cells, CD11c+ CD11b+ cells isolated from TPL-2-deficient mice had elevated Ccl24. Finally, Ccl24 neutralization in TPL-2 deficient mice significantly decreased the expression of Arg1, Retnla, Chil3 and Ear11 correlating with a loss of resistance to H. polygyrus. These observations suggest that TPL-2-regulated Ccl24 in CD11c+CD11b+ cells prevents accelerated type-2 mediated immunity to H. polygyrus. Collectively, this study identifies a previously unappreciated role for TPL-2 controlling immune responses to H. polygyrus infection by restricting Ccl24 production.

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