MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase

Soaring rates of systemic fungal infections worldwide underscore the need for vaccine prevention. An understanding of the elements that promote vaccine immunity is essential. We previously reported that Th17 cells are required for vaccine immunity to the systemic dimorphic fungi of North America, an...

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Main Authors:	Wang, Huafeng, Li, Mengyi, Hung, Chiung Yu, Sinha, Meenal, Lee, Linda M., Wiesner, Darin L., LeBert, Vanessa, Lerksuthirat, Tassanee, Galles, Kevin, Suresh, Marulasiddappa, DeFranco, Anthony L., Lowell, Clifford A., Klein, Bruce S., Wüthrich, Marcel
Format:	Online
Language:	English
Published:	Public Library of Science 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991787/

id	pubmed-4991787
recordtype	oai_dc
spelling	pubmed-49917872016-09-12 MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase Wang, Huafeng Li, Mengyi Hung, Chiung Yu Sinha, Meenal Lee, Linda M. Wiesner, Darin L. LeBert, Vanessa Lerksuthirat, Tassanee Galles, Kevin Suresh, Marulasiddappa DeFranco, Anthony L. Lowell, Clifford A. Klein, Bruce S. Wüthrich, Marcel Research Article Soaring rates of systemic fungal infections worldwide underscore the need for vaccine prevention. An understanding of the elements that promote vaccine immunity is essential. We previously reported that Th17 cells are required for vaccine immunity to the systemic dimorphic fungi of North America, and that Card9 and MyD88 signaling are required for the development of protective Th17 cells. Herein, we investigated where, when and how MyD88 regulates T cell development. We uncovered a novel mechanism in which MyD88 extrinsically regulates the survival of activated T cells during the contraction phase and in the absence of inflammation, but is dispensable for the expansion and differentiation of the cells. The poor survival of activated T cells in Myd88 -/- mice is linked to increased caspase3-mediated apoptosis, but not to Fas- or Bim-dependent apoptotic pathways, nor to reduced expression of the anti-apoptotic molecules Bcl-2 or Bcl-xL. Moreover, TLR3, 7, and/or 9, but not TLR2 or 4, also were required extrinsically for MyD88-dependent Th17 cell responses and vaccine immunity. Similar MyD88 requirements governed the survival of virus primed T cells. Our data identify unappreciated new requirements for eliciting adaptive immunity and have implications for designing vaccines. Public Library of Science 2016-08-19 /pmc/articles/PMC4991787/ /pubmed/27542117 http://dx.doi.org/10.1371/journal.ppat.1005787 Text en © 2016 Wang 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	Wang, Huafeng Li, Mengyi Hung, Chiung Yu Sinha, Meenal Lee, Linda M. Wiesner, Darin L. LeBert, Vanessa Lerksuthirat, Tassanee Galles, Kevin Suresh, Marulasiddappa DeFranco, Anthony L. Lowell, Clifford A. Klein, Bruce S. Wüthrich, Marcel
spellingShingle	Wang, Huafeng Li, Mengyi Hung, Chiung Yu Sinha, Meenal Lee, Linda M. Wiesner, Darin L. LeBert, Vanessa Lerksuthirat, Tassanee Galles, Kevin Suresh, Marulasiddappa DeFranco, Anthony L. Lowell, Clifford A. Klein, Bruce S. Wüthrich, Marcel MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase
author_facet	Wang, Huafeng Li, Mengyi Hung, Chiung Yu Sinha, Meenal Lee, Linda M. Wiesner, Darin L. LeBert, Vanessa Lerksuthirat, Tassanee Galles, Kevin Suresh, Marulasiddappa DeFranco, Anthony L. Lowell, Clifford A. Klein, Bruce S. Wüthrich, Marcel
author_sort	Wang, Huafeng
title	MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase
title_short	MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase
title_full	MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase
title_fullStr	MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase
title_full_unstemmed	MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase
title_sort	myd88 shapes vaccine immunity by extrinsically regulating survival of cd4+ t cells during the contraction phase
description	Soaring rates of systemic fungal infections worldwide underscore the need for vaccine prevention. An understanding of the elements that promote vaccine immunity is essential. We previously reported that Th17 cells are required for vaccine immunity to the systemic dimorphic fungi of North America, and that Card9 and MyD88 signaling are required for the development of protective Th17 cells. Herein, we investigated where, when and how MyD88 regulates T cell development. We uncovered a novel mechanism in which MyD88 extrinsically regulates the survival of activated T cells during the contraction phase and in the absence of inflammation, but is dispensable for the expansion and differentiation of the cells. The poor survival of activated T cells in Myd88 -/- mice is linked to increased caspase3-mediated apoptosis, but not to Fas- or Bim-dependent apoptotic pathways, nor to reduced expression of the anti-apoptotic molecules Bcl-2 or Bcl-xL. Moreover, TLR3, 7, and/or 9, but not TLR2 or 4, also were required extrinsically for MyD88-dependent Th17 cell responses and vaccine immunity. Similar MyD88 requirements governed the survival of virus primed T cells. Our data identify unappreciated new requirements for eliciting adaptive immunity and have implications for designing vaccines.
publisher	Public Library of Science
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991787/
_version_	1613631035457667072

MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase

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