title: Intrinsic MyD88-Akt1-mTOR Signaling Coordinates Disparate Tc17 and Tc1 Responses during Vaccine Immunity against Fungal Pneumonia.
abstract: Fungal infections have skyrocketed in immune-compromised patients lacking CD4+ T cells, underscoring the need for vaccine prevention. An understanding of the elements that promote vaccine immunity in this setting is essential. We previously demonstrated that vaccine-induced IL-17A+ CD8+ T cells (Tc17) are required for resistance against lethal fungal pneumonia in CD4+ T cell-deficient hosts, whereas the individual type I cytokines IFN-γ, TNF-α and GM-CSF, are dispensable. Here, we report that T cell-intrinsic MyD88 signals are crucial for these Tc17 cell responses and vaccine immunity against lethal fungal pneumonia in mice. In contrast, IFN-γ+ CD8+ cell (Tc1) responses are largely normal in the absence of intrinsic MyD88 signaling in CD8+ T cells. The poor accumulation of MyD88-deficient Tc17 cells was not linked to an early onset of contraction, nor to accelerated cell death or diminished expression of anti-apoptotic molecules Bcl-2 or Bcl-xL. Instead, intrinsic MyD88 was required to sustain the proliferation of Tc17 cells through the activation of mTOR via Akt1. Moreover, intrinsic IL-1R and TLR2, but not IL-18R, were required for MyD88 dependent Tc17 responses. Our data identify unappreciated targets for augmenting adaptive immunity against fungi. Our findings have implications for designing fungal vaccines and immune-based therapies in immune-compromised patients.
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Som Gowda
authors.initials: SG
authors.lastname: Nanjappa
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Nydiaris
authors.initials: N
authors.lastname: Hernández-Santos
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Galles
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Marcel
authors.initials: M
authors.lastname: Wüthrich
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: M
authors.initials: M
authors.lastname: Suresh
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America; Department of Internal Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America; Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Klein
mesh_terms: D000818:Animals; D001758:Blastomyces / Q000276:immunology* / Q000502:physiology; D001759:Blastomycosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005657:Fungal Vaccines / Q000627:therapeutic use*; D007156:Immunologic Memory; D008212:Lymphocyte Depletion; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000378:metabolism
chemical_list: D005657:Fungal Vaccines; C583355:IL1R1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053573:Receptors, Interleukin-1 Type I; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases