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    Rights statement: © 2013 Worthington et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Loss of the TGFβ-activating integrin αvβ8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity

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Loss of the TGFβ-activating integrin αvβ8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity. / Worthington, John J.; Klementowicz, Joanna E.; Rahman, Sayema; Czajkowska, Beata I.; Smedley, Catherine; Waldmann, Herman; Sparwasser, Tim; Grencis, Richard K.; Travis, Mark A.

In: PLoS Pathogens, Vol. 9, No. 10, e1003675, 2013.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Worthington, JJ, Klementowicz, JE, Rahman, S, Czajkowska, BI, Smedley, C, Waldmann, H, Sparwasser, T, Grencis, RK & Travis, MA 2013, 'Loss of the TGFβ-activating integrin αvβ8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity', PLoS Pathogens, vol. 9, no. 10, e1003675. https://doi.org/10.1371/journal.ppat.1003675

APA

Worthington, J. J., Klementowicz, J. E., Rahman, S., Czajkowska, B. I., Smedley, C., Waldmann, H., Sparwasser, T., Grencis, R. K., & Travis, M. A. (2013). Loss of the TGFβ-activating integrin αvβ8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity. PLoS Pathogens, 9(10), [e1003675]. https://doi.org/10.1371/journal.ppat.1003675

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Author

Worthington, John J. ; Klementowicz, Joanna E. ; Rahman, Sayema ; Czajkowska, Beata I. ; Smedley, Catherine ; Waldmann, Herman ; Sparwasser, Tim ; Grencis, Richard K. ; Travis, Mark A. / Loss of the TGFβ-activating integrin αvβ8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity. In: PLoS Pathogens. 2013 ; Vol. 9, No. 10.

Bibtex

@article{a551238182594930b42fd505f6143058,
title = "Loss of the TGFβ-activating integrin αvβ8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity",
abstract = "Chronic intestinal parasite infection is a major global health problem, but mechanisms that promote chronicity are poorly understood. Here we describe a novel cellular and molecular pathway involved in the development of chronic intestinal parasite infection. We show that, early during development of chronic infection with the murine intestinal parasite Trichuris muris, TGFβ signalling in CD4+ T-cells is induced and that antibody-mediated inhibition of TGFβ function results in protection from infection. Mechanistically, we find that enhanced TGFβ signalling in CD4+ T-cells during infection involves expression of the TGFβ-activating integrin αvβ8 by dendritic cells (DCs), which we have previously shown is highly expressed by a subset of DCs in the intestine. Importantly, mice lacking integrin αvβ8 on DCs were completely resistant to chronic infection with T. muris, indicating an important functional role for integrin αvβ8-mediated TGFβ activation in promoting chronic infection. Protection from infection was dependent on CD4+ T-cells, but appeared independent of Foxp3+ Tregs. Instead, mice lacking integrin αvβ8 expression on DCs displayed an early increase in production of the protective type 2 cytokine IL-13 by CD4+ T-cells, and inhibition of this increase by crossing mice to IL-4 knockout mice restored parasite infection. Our results therefore provide novel insights into how type 2 immunity is controlled in the intestine, and may help contribute to development of new therapies aimed at promoting expulsion of gut helminths.",
keywords = "Animals, Chronic Disease, Dendritic Cells, Integrins, Interleukin-13, Intestinal Diseases, Parasitic, Mice, Mice, Knockout, Th2 Cells, Transforming Growth Factor beta, Trichuriasis, Trichuris",
author = "Worthington, {John J.} and Klementowicz, {Joanna E.} and Sayema Rahman and Czajkowska, {Beata I.} and Catherine Smedley and Herman Waldmann and Tim Sparwasser and Grencis, {Richard K.} and Travis, {Mark A.}",
note = "{\textcopyright} 2013 Worthington et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
year = "2013",
doi = "10.1371/journal.ppat.1003675",
language = "English",
volume = "9",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "10",

}

RIS

TY - JOUR

T1 - Loss of the TGFβ-activating integrin αvβ8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity

AU - Worthington, John J.

AU - Klementowicz, Joanna E.

AU - Rahman, Sayema

AU - Czajkowska, Beata I.

AU - Smedley, Catherine

AU - Waldmann, Herman

AU - Sparwasser, Tim

AU - Grencis, Richard K.

AU - Travis, Mark A.

N1 - © 2013 Worthington et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2013

Y1 - 2013

N2 - Chronic intestinal parasite infection is a major global health problem, but mechanisms that promote chronicity are poorly understood. Here we describe a novel cellular and molecular pathway involved in the development of chronic intestinal parasite infection. We show that, early during development of chronic infection with the murine intestinal parasite Trichuris muris, TGFβ signalling in CD4+ T-cells is induced and that antibody-mediated inhibition of TGFβ function results in protection from infection. Mechanistically, we find that enhanced TGFβ signalling in CD4+ T-cells during infection involves expression of the TGFβ-activating integrin αvβ8 by dendritic cells (DCs), which we have previously shown is highly expressed by a subset of DCs in the intestine. Importantly, mice lacking integrin αvβ8 on DCs were completely resistant to chronic infection with T. muris, indicating an important functional role for integrin αvβ8-mediated TGFβ activation in promoting chronic infection. Protection from infection was dependent on CD4+ T-cells, but appeared independent of Foxp3+ Tregs. Instead, mice lacking integrin αvβ8 expression on DCs displayed an early increase in production of the protective type 2 cytokine IL-13 by CD4+ T-cells, and inhibition of this increase by crossing mice to IL-4 knockout mice restored parasite infection. Our results therefore provide novel insights into how type 2 immunity is controlled in the intestine, and may help contribute to development of new therapies aimed at promoting expulsion of gut helminths.

AB - Chronic intestinal parasite infection is a major global health problem, but mechanisms that promote chronicity are poorly understood. Here we describe a novel cellular and molecular pathway involved in the development of chronic intestinal parasite infection. We show that, early during development of chronic infection with the murine intestinal parasite Trichuris muris, TGFβ signalling in CD4+ T-cells is induced and that antibody-mediated inhibition of TGFβ function results in protection from infection. Mechanistically, we find that enhanced TGFβ signalling in CD4+ T-cells during infection involves expression of the TGFβ-activating integrin αvβ8 by dendritic cells (DCs), which we have previously shown is highly expressed by a subset of DCs in the intestine. Importantly, mice lacking integrin αvβ8 on DCs were completely resistant to chronic infection with T. muris, indicating an important functional role for integrin αvβ8-mediated TGFβ activation in promoting chronic infection. Protection from infection was dependent on CD4+ T-cells, but appeared independent of Foxp3+ Tregs. Instead, mice lacking integrin αvβ8 expression on DCs displayed an early increase in production of the protective type 2 cytokine IL-13 by CD4+ T-cells, and inhibition of this increase by crossing mice to IL-4 knockout mice restored parasite infection. Our results therefore provide novel insights into how type 2 immunity is controlled in the intestine, and may help contribute to development of new therapies aimed at promoting expulsion of gut helminths.

KW - Animals

KW - Chronic Disease

KW - Dendritic Cells

KW - Integrins

KW - Interleukin-13

KW - Intestinal Diseases, Parasitic

KW - Mice

KW - Mice, Knockout

KW - Th2 Cells

KW - Transforming Growth Factor beta

KW - Trichuriasis

KW - Trichuris

U2 - 10.1371/journal.ppat.1003675

DO - 10.1371/journal.ppat.1003675

M3 - Journal article

C2 - 24098124

VL - 9

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 10

M1 - e1003675

ER -