title: Effector T Cells and Ischemia-Induced Systemic Angiogenesis in the Lung.
abstract: Lymphocytes have been shown to modulate angiogenesis. Our previous work showed that T regulatory (Treg) cell depletion prevented angiogenesis. In the present study, we sought to examine T-cell populations during lung angiogenesis and subsequent angiostasis. In a mouse model of ischemia-induced systemic angiogenesis in the lung, we examined the time course (0-35 d) of neovascularization and T-cell phenotypes within the lung after left pulmonary artery ligation (LPAL). T cells increased and reached a maximum by 10 days after LPAL and then progressively decreased, suggestive of a modulatory role during the early phase of new vessel growth. Because others have shown IFN-γ to be angiostatic in tumor models, we focused on this effector T-cell cytokine to control the magnitude of angiogenesis. Results showed that IFN-γ protein is secreted at low levels after LPAL and that mice required Treg depletion to see the full effect of effector T cells. Using Foxp3(DTR) and diphtheria toxin to deplete T regulatory cells, increased numbers of effector T cells (CD8(+)) and/or increased capacity to secrete the prominent angiostatic cytokine IFN-γ (CD4(+)) were seen. In vitro culture of mouse systemic and pulmonary microvascular endothelial cells with IFN-γ showed increased endothelial cell apoptosis. CD8(-/-) mice and IFN-γR(-/-) mice showed enhanced angiogenesis compared with wild-type mice, confirming that, in this model, IFN-γ limits the extent of systemic neovascularization in the lung.
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: John
authors.initials: J
authors.lastname: Jenkins
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Aigul
authors.initials: A
authors.lastname: Moldobaeva
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Franco
authors.initials: F
authors.lastname: D'Alessio
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wagner
mesh_terms: D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007511:Ischemia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D010641:Phenotype; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D000096743:Interferon gamma Receptor
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C498833:Foxp3 protein, mouse
keywords: IFN-γ; angiogenesis; angiostasis; ischemia; regulatory T-cells