title: IL-12 is required for differentiation of pathogenic CD8+ T cell effectors that cause myocarditis.
abstract: Cardiac antigen-specific CD8(+) T cells are involved in the autoimmune component of human myocarditis. Here, we studied the differentiation and migration of pathogenic CD8(+) T cell effector cells in a new mouse model of autoimmune myocarditis. A transgenic mouse line was derived that expresses cardiac myocyte restricted membrane-bound ovalbumin (CMy-mOva). The endogenous adaptive immune system of CMy-mOva mice displays tolerance to ovalbumin. Adoptive transfer of naive CD8(+) T cells from the ovalbumin-specific T cell receptor-transgenic (TCR-transgenic) OT-I strain induces myocarditis in CMy-mOva mice only after subsequent inoculation with ovalbumin-expressing vesicular stomatitis virus (VSV-Ova). OT-I effector T cells derived in vitro in the presence or absence of IL-12 were adoptively transferred into CMy-mOva mice, and the consequences were compared. Although IL-12 was not required for the generation of cytolytic and IFN-gamma-producing effector T cells, only effectors primed in the presence of IL-12 infiltrated CMy-mOva hearts in significant numbers, causing lethal myocarditis. Furthermore, analysis of OT-I effectors collected from a mediastinal draining lymph node indicated that only effectors primed in vitro in the presence of IL-12 proliferated in vivo. These data demonstrate the importance of IL-12 in the differentiation of pathogenic CD8(+) T cells that can cause myocarditis.
authors.affiliation: Immunology Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Grabie
authors.forename: Michael W
authors.initials: MW
authors.lastname: Delfs
authors.forename: Jason R
authors.initials: JR
authors.lastname: Westrich
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Love
authors.forename: George
authors.initials: G
authors.lastname: Stavrakis
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000209:etiology* / Q000276:immunology; D009928:Organ Specificity; D010047:Ovalbumin / Q000276:immunology
chemical_list: D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin