title: MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase.
abstract: 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.
authors.affiliation: Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Mengyi
authors.identifier: 0000-0001-6514-1793
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Chiung Yu
authors.initials: CY
authors.lastname: Hung
authors.affiliation: Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Meenal
authors.initials: M
authors.lastname: Sinha
authors.affiliation: Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Lee
authors.affiliation: Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Darin L
authors.initials: DL
authors.lastname: Wiesner
authors.affiliation: Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Vanessa
authors.initials: V
authors.lastname: LeBert
authors.affiliation: Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Tassanee
authors.initials: T
authors.lastname: Lerksuthirat
authors.affiliation: Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Kevin
authors.identifier: 0000-0002-9797-9109
authors.initials: K
authors.lastname: Galles
authors.affiliation: Department of Pathobiological Sciences, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Marulasiddappa
authors.initials: M
authors.lastname: Suresh
authors.affiliation: Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: DeFranco
authors.affiliation: Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.affiliation: Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Internal Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Klein
authors.affiliation: Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Marcel
authors.initials: M
authors.lastname: Wüthrich
mesh_terms: D000818:Animals; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000276:immunology; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D005657:Fungal Vaccines / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009181:Mycoses / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
chemical_list: D000072224:Bcl-2-Like Protein 11; C494812:Bcl2l1 protein, mouse; C000606776:Bcl2l11 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C513280:Card9 protein, mouse; C491899:Fas protein, mouse; D005657:Fungal Vaccines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D019253:Proto-Oncogene Proteins c-bcl-2; D051193:Toll-Like Receptors; D051020:bcl-X Protein; D019014:fas Receptor; C052617:Bcl2 protein, mouse