Effector T Cells and Ischemia-Induced Systemic Angiogenesis in the Lung

Am J Respir Cell Mol Biol. 2016 Mar;54(3):394-401. doi: 10.1165/rcmb.2015-0087OC.

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.

Keywords: IFN-γ; angiogenesis; angiostasis; ischemia; regulatory T-cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • CD4 Antigens / genetics
  • CD4 Antigens / immunology
  • CD4 Antigens / metabolism
  • CD8 Antigens / genetics
  • CD8 Antigens / immunology
  • CD8 Antigens / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells / immunology*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Ischemia / genetics
  • Ischemia / immunology*
  • Ischemia / metabolism
  • Ischemia / pathology
  • Ischemia / physiopathology
  • Lung / blood supply*
  • Lung / immunology*
  • Lung / metabolism
  • Lung / pathology
  • Lymphocyte Activation
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Physiologic*
  • Phenotype
  • Receptors, Interferon / genetics
  • Receptors, Interferon / immunology
  • Receptors, Interferon / metabolism
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Time Factors

Substances

  • CD4 Antigens
  • CD8 Antigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Interferon
  • interferon gamma receptor
  • Interferon-gamma