IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.

The IL-27R, WSX-1, is required to limit IFN-γ production by effector CD4⁺ T cells in a number of different inflammatory conditions but the molecular basis of WSX-1-mediated regulation of Th1 responses in vivo during infection has not been investigated in detail. In this study we demonstrate that WSX...

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Autores principales:	Ana Villegas-Mendez, J Brian de Souza, Seen-Wai Lavelle, Emily Gwyer Findlay, Tovah N Shaw, Nico van Rooijen, Christiaan J Saris, Christopher A Hunter, Eleanor M Riley, Kevin N Couper
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/0a9fcc6cf8cd4e8ca876915393761c65
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spelling	oai:doaj.org-article:0a9fcc6cf8cd4e8ca876915393761c652021-11-18T06:05:47ZIL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.1553-73661553-737410.1371/journal.ppat.1003293https://doaj.org/article/0a9fcc6cf8cd4e8ca876915393761c652013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23593003/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The IL-27R, WSX-1, is required to limit IFN-γ production by effector CD4⁺ T cells in a number of different inflammatory conditions but the molecular basis of WSX-1-mediated regulation of Th1 responses in vivo during infection has not been investigated in detail. In this study we demonstrate that WSX-1 signalling suppresses the development of pathogenic, terminally differentiated (KLRG-1⁺) Th1 cells during malaria infection and establishes a restrictive threshold to constrain the emergent Th1 response. Importantly, we show that WSX-1 regulates cell-intrinsic responsiveness to IL-12 and IL-2, but the fate of the effector CD4⁺ T cell pool during malaria infection is controlled primarily through IL-12 dependent signals. Finally, we show that WSX-1 regulates Th1 cell terminal differentiation during malaria infection through IL-10 and Foxp3 independent mechanisms; the kinetics and magnitude of the Th1 response, and the degree of Th1 cell terminal differentiation, were comparable in WT, IL-10R1⁻/⁻ and IL-10⁻/⁻ mice and the numbers and phenotype of Foxp3⁺ cells were largely unaltered in WSX-1⁻/⁻ mice during infection. As expected, depletion of Foxp3⁺ cells did not enhance Th1 cell polarisation or terminal differentiation during malaria infection. Our results significantly expand our understanding of how IL-27 regulates Th1 responses in vivo during inflammatory conditions and establishes WSX-1 as a critical and non-redundant regulator of the emergent Th1 effector response during malaria infection.Ana Villegas-MendezJ Brian de SouzaSeen-Wai LavelleEmily Gwyer FindlayTovah N ShawNico van RooijenChristiaan J SarisChristopher A HunterEleanor M RileyKevin N CouperPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 4, p e1003293 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Ana Villegas-Mendez J Brian de Souza Seen-Wai Lavelle Emily Gwyer Findlay Tovah N Shaw Nico van Rooijen Christiaan J Saris Christopher A Hunter Eleanor M Riley Kevin N Couper IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.
description	The IL-27R, WSX-1, is required to limit IFN-γ production by effector CD4⁺ T cells in a number of different inflammatory conditions but the molecular basis of WSX-1-mediated regulation of Th1 responses in vivo during infection has not been investigated in detail. In this study we demonstrate that WSX-1 signalling suppresses the development of pathogenic, terminally differentiated (KLRG-1⁺) Th1 cells during malaria infection and establishes a restrictive threshold to constrain the emergent Th1 response. Importantly, we show that WSX-1 regulates cell-intrinsic responsiveness to IL-12 and IL-2, but the fate of the effector CD4⁺ T cell pool during malaria infection is controlled primarily through IL-12 dependent signals. Finally, we show that WSX-1 regulates Th1 cell terminal differentiation during malaria infection through IL-10 and Foxp3 independent mechanisms; the kinetics and magnitude of the Th1 response, and the degree of Th1 cell terminal differentiation, were comparable in WT, IL-10R1⁻/⁻ and IL-10⁻/⁻ mice and the numbers and phenotype of Foxp3⁺ cells were largely unaltered in WSX-1⁻/⁻ mice during infection. As expected, depletion of Foxp3⁺ cells did not enhance Th1 cell polarisation or terminal differentiation during malaria infection. Our results significantly expand our understanding of how IL-27 regulates Th1 responses in vivo during inflammatory conditions and establishes WSX-1 as a critical and non-redundant regulator of the emergent Th1 effector response during malaria infection.
format	article
author	Ana Villegas-Mendez J Brian de Souza Seen-Wai Lavelle Emily Gwyer Findlay Tovah N Shaw Nico van Rooijen Christiaan J Saris Christopher A Hunter Eleanor M Riley Kevin N Couper
author_facet	Ana Villegas-Mendez J Brian de Souza Seen-Wai Lavelle Emily Gwyer Findlay Tovah N Shaw Nico van Rooijen Christiaan J Saris Christopher A Hunter Eleanor M Riley Kevin N Couper
author_sort	Ana Villegas-Mendez
title	IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.
title_short	IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.
title_full	IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.
title_fullStr	IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.
title_full_unstemmed	IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.
title_sort	il-27 receptor signalling restricts the formation of pathogenic, terminally differentiated th1 cells during malaria infection by repressing il-12 dependent signals.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/0a9fcc6cf8cd4e8ca876915393761c65
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IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.

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