title: CTLA-4 ablation and interleukin-12 driven differentiation synergistically augment cardiac pathogenicity of cytotoxic T lymphocytes.
abstract: CD8+ cytotoxic T lymphocytes contribute to viral and autoimmune myocarditis and cardiac allograft rejection. The role of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 as a negative regulator of CD4+ T cells is well defined, yet CTLA-4 regulation of CD8+ T cells is less clear. We studied CTLA-4 regulation of cytotoxic T lymphocytes in a transgenic model of CD8+ T-cell-mediated myocarditis. We generated CTLA-4(-/-) Rag 2(-/-) OT-1 mice, the CD8+ T cells of which express an ovalbumin (OVA) peptide-specific, class I major histocompatibility complex-restricted T-cell receptor. CTLA-4(-/-Tc12) OT-1 effectors, differentiated with interleukin-12 present, are hyperproliferative in vitro, compared with CTLA-4(+/+)Tc12 OT-1 controls. Transfer of low doses of CTLA-4(-/-Tc12) OT-1 cells to cMy-mOVA mice, which express OVA on cardiac myocytes, causes severe myocarditis, with 99% mortality, compared with no mortality after transfer of low doses of CTLA-4(+/+)Tc12 OT-1 cells. High doses of CTLA-4(+/+)Tc12 cells cause lethal myocarditis in cMy-mOVA mice, but high doses of CTLA-4(+/+)Tc0 CTL, generated without interleukin-12, are hypoproliferative within the cardiac-draining lymph node and do not significantly infiltrate the heart. In contrast, CTLA-4(-/-Tc0) cytotoxic T lymphocytes do proliferate in the cardiac-draining lymph node and diffusely infiltrate the heart. Nonetheless, high doses of CTLA-4(-/-Tc0) cells cause only limited tissue damage, and the disease is not lethal. These data show that CTLA-4 regulates myocarditic CD8+ T cell responses and that CTLA-4 deficiency partly overcomes a differentiation block that exists when naïve CD8+ T cells are stimulated without interleukin-12. Therefore, targeting CTLA-4 solely or in conjunction with interleukin-12 could influence effector CD8+ T cell responses in therapeutically beneficial ways.
authors.affiliation: Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Love
authors.forename: Nir
authors.initials: N
authors.lastname: Grabie
authors.forename: Paurene
authors.initials: P
authors.lastname: Duramad
authors.forename: George
authors.initials: G
authors.lastname: Stavrakis
authors.forename: Arlene
authors.initials: A
authors.lastname: Sharpe
authors.forename: Andrew
authors.initials: A
authors.lastname: Lichtman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D060908:CTLA-4 Antigen; D002454:Cell Differentiation; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004527:Egg Proteins / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000502:physiology*; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D009205:Myocarditis / Q000276:immunology / Q000503:physiopathology* / Q000517:prevention & control; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity; D010446:Peptide Fragments; D013047:Specific Pathogen-Free Organisms; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D004268:DNA-Binding Proteins; D004527:Egg Proteins; D008222:Lymphokines; C110366:OVA-8; D010446:Peptide Fragments; C499308:Rag2 protein, mouse; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin