title: Pathogenic IL-23 signaling is required to initiate GM-CSF-driven autoimmune myocarditis in mice.
abstract: Using a mouse model of experimental autoimmune myocarditis (EAM), we showed for the first time that IL-23 stimulation of CD4(+) T cells is required only briefly at the initiation of GM-CFS-dependent cardiac autoimmunity. IL-23 signal, acting as a switch, turns on pathogenicity of CD4(+) T cells, and becomes dispensable once autoreactivity is established. Il23a(-/-) mice failed to mount an efficient Th17 response to immunization, and were protected from myocarditis. However, remarkably, transient IL-23 stimulation ex vivo fully restored pathogenicity in otherwise nonpathogenic CD4(+) T cells raised from Il23a(-/-) donors. Thus, IL-23 may no longer be necessary to uphold inflammation in established autoimmune diseases. In addition, we demonstrated that IL-23-induced GM-CSF mediates the pathogenicity of CD4(+) T cells in EAM. The neutralization of GM-CSF abrogated cardiac inflammation. However, sustained IL-23 signaling is required to maintain IL-17A production in CD4(+) T cells. Despite inducing inflammation in Il23a(-/-) recipients comparable to wild-type (WT), autoreactive CD4(+) T cells downregulated IL-17A production without persistent IL-23 signaling. This divergence on the controls of GM-CSF-dependent pathogenicity on one side and IL-17A production on the other side may contribute to the discrepant efficacies of anti-IL-23 therapy in different autoimmune diseases.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Diny
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: SuFey
authors.initials: S
authors.lastname: Ong
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jobert G
authors.initials: JG
authors.lastname: Barin
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Xuezhou
authors.initials: X
authors.lastname: Hou
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.|Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Noel R
authors.initials: NR
authors.lastname: Rose
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Monica V
authors.initials: MV
authors.lastname: Talor
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.|Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Čiháková
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D053759:Interleukin-23 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009205:Myocarditis / Q000276:immunology* / Q000503:physiopathology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Autoimmunity; GM-CSF; IL-17A; IL-23; Myocarditis; Th17