title: CD11b+ monocytes abrogate Th17 CD4+ T cell-mediated experimental autoimmune myocarditis.
abstract: Experimental autoimmune myocarditis (EAM) represents a Th17 T cell-mediated mouse model of postinflammatory heart disease. In BALB/c wild-type mice, EAM is a self-limiting disease, peaking 21 days after alpha-myosin H chain peptide (MyHC-alpha)/CFA immunization and largely resolving thereafter. In IFN-gammaR(-/-) mice, however, EAM is exacerbated and shows a chronic progressive disease course. We found that this progressive disease course paralleled persistently elevated IL-17 release from T cells infiltrating the hearts of IFN-gammaR(-/-) mice 30 days after immunization. In fact, IL-17 promoted the recruitment of CD11b(+) monocytes, the major heart-infiltrating cells in EAM. In turn, CD11b(+) monocytes suppressed MyHC-alpha-specific Th17 T cell responses IFN-gamma-dependently in vitro. In vivo, injection of IFN-gammaR(+/+)CD11b(+), but not IFN-gammaR(-/-)CD11b(+), monocytes, suppressed MyHC-alpha-specific T cells, and abrogated the progressive disease course in IFN-gammaR(-/-) mice. Finally, coinjection of MyHC-alpha-specific, but not OVA-transgenic, IFN-gamma-releasing CD4(+) Th1 T cell lines, together with MyHC-alpha-specific Th17 T cells protected RAG2(-/-) mice from EAM. In conclusion, CD11b(+) monocytes play a dual role in EAM: as a major cellular substrate of IL-17-induced inflammation and as mediators of an IFN-gamma-dependent negative feedback loop confining disease progression.
authors.affiliation: Experimental Critical Care Medicine, Department of Research, University Hospital, Petersgraben 4, Basel, Switzerland.
authors.forename: Alan
authors.initials: A
authors.lastname: Valaperti
authors.forename: René R
authors.initials: RR
authors.lastname: Marty
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kania
authors.forename: Davide
authors.initials: D
authors.lastname: Germano
authors.forename: Nora
authors.initials: N
authors.lastname: Mauermann
authors.forename: Stefan
authors.initials: S
authors.lastname: Dirnhofer
authors.forename: Bernd
authors.initials: B
authors.lastname: Leimenstoll
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Blyszczuk
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.forename: Christian
authors.initials: C
authors.lastname: Mueller
authors.forename: Lukas
authors.initials: L
authors.lastname: Hunziker
authors.forename: Urs
authors.initials: U
authors.lastname: Eriksson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000473:pathology / Q000517:prevention & control*; D039481:CD11b Antigen / Q000096:biosynthesis*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D002469:Cell Separation; D018450:Disease Progression; D025461:Feedback, Physiological / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D020381:Interleukin-17 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009205:Myocarditis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D018417:Th1 Cells / Q000276:immunology
chemical_list: D039481:CD11b Antigen; D007106:Immune Sera; D020381:Interleukin-17