Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection

The suppression of protective Type 2 immunity is a principal factor driving the chronicity of helminth infections, and has been attributed to a range of Th2 cell-extrinsic immune-regulators. However, the intrinsic fate of parasite-specific Th2 cells within a chronic immune down-regulatory environmen...

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Main Authors:	van der Werf, Nienke, Redpath, Stephen A., Azuma, Miyuki, Yagita, Hideo, Taylor, Matthew D.
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597521/

id	pubmed-3597521
recordtype	oai_dc
spelling	pubmed-35975212013-03-20 Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection van der Werf, Nienke Redpath, Stephen A. Azuma, Miyuki Yagita, Hideo Taylor, Matthew D. Research Article The suppression of protective Type 2 immunity is a principal factor driving the chronicity of helminth infections, and has been attributed to a range of Th2 cell-extrinsic immune-regulators. However, the intrinsic fate of parasite-specific Th2 cells within a chronic immune down-regulatory environment, and the resultant impact such fate changes may have on host resistance is unknown. We used IL-4gfp reporter mice to demonstrate that during chronic helminth infection with the filarial nematode Litomosoides sigmodontis, CD4+ Th2 cells are conditioned towards an intrinsically hypo-responsive phenotype, characterised by a loss of functional ability to proliferate and produce the cytokines IL-4, IL-5 and IL-2. Th2 cell hypo-responsiveness was a key element determining susceptibility to L. sigmodontis infection, and could be reversed in vivo by blockade of PD-1 resulting in long-term recovery of Th2 cell functional quality and enhanced resistance. Contrasting with T cell dysfunction in Type 1 settings, the control of Th2 cell hypo-responsiveness by PD-1 was mediated through PD-L2, and not PD-L1. Thus, intrinsic changes in Th2 cell quality leading to a functionally hypo-responsive phenotype play a key role in determining susceptibility to filarial infection, and the therapeutic manipulation of Th2 cell-intrinsic quality provides a potential avenue for promoting resistance to helminths. Public Library of Science 2013-03-14 /pmc/articles/PMC3597521/ /pubmed/23516361 http://dx.doi.org/10.1371/journal.ppat.1003215 Text en © 2013 van der Werf et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	van der Werf, Nienke Redpath, Stephen A. Azuma, Miyuki Yagita, Hideo Taylor, Matthew D.
spellingShingle	van der Werf, Nienke Redpath, Stephen A. Azuma, Miyuki Yagita, Hideo Taylor, Matthew D. Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection
author_facet	van der Werf, Nienke Redpath, Stephen A. Azuma, Miyuki Yagita, Hideo Taylor, Matthew D.
author_sort	van der Werf, Nienke
title	Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection
title_short	Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection
title_full	Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection
title_fullStr	Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection
title_full_unstemmed	Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection
title_sort	th2 cell-intrinsic hypo-responsiveness determines susceptibility to helminth infection
description	The suppression of protective Type 2 immunity is a principal factor driving the chronicity of helminth infections, and has been attributed to a range of Th2 cell-extrinsic immune-regulators. However, the intrinsic fate of parasite-specific Th2 cells within a chronic immune down-regulatory environment, and the resultant impact such fate changes may have on host resistance is unknown. We used IL-4gfp reporter mice to demonstrate that during chronic helminth infection with the filarial nematode Litomosoides sigmodontis, CD4+ Th2 cells are conditioned towards an intrinsically hypo-responsive phenotype, characterised by a loss of functional ability to proliferate and produce the cytokines IL-4, IL-5 and IL-2. Th2 cell hypo-responsiveness was a key element determining susceptibility to L. sigmodontis infection, and could be reversed in vivo by blockade of PD-1 resulting in long-term recovery of Th2 cell functional quality and enhanced resistance. Contrasting with T cell dysfunction in Type 1 settings, the control of Th2 cell hypo-responsiveness by PD-1 was mediated through PD-L2, and not PD-L1. Thus, intrinsic changes in Th2 cell quality leading to a functionally hypo-responsive phenotype play a key role in determining susceptibility to filarial infection, and the therapeutic manipulation of Th2 cell-intrinsic quality provides a potential avenue for promoting resistance to helminths.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597521/
_version_	1611962091144478720

Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection

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