title: Lung Angiogenesis Requires CD4(+) Forkhead Homeobox Protein-3(+) Regulatory T Cells.
abstract: Angiogenesis in ischemic organs is modulated by immune cells. Systemic neovascularization of the ischemic lung requires macrophages, with chemokines playing a central role in new vessel growth. Because regulatory T (Treg) cells modulate tumor-induced neovascularization, we questioned whether this CD4(+) lymphocyte subset impacts blood vessel growth during ischemia. In a model of left lung ischemia, an increase in CD4(+) CD25(+) forkhead homeobox protein-3 (Foxp3)(+) cells was observed 3-5 days after the onset of ischemia in wild-type C57Bl/6 mice. Using transgenic mice where Foxp3(+) Treg cells can be depleted with diphtheria toxin (DT; Foxp3(DTR)), we unexpectedly found that Foxp3(+) Treg depletion led to markedly reduced lung angiogenesis (90% reduction from Foxp3(gfp) controls). Adoptive transfer studies using CD4(+) CD25(+) splenocytes from congenic CD45.1 mice into Foxp3(+) Treg-depleted mice showed an almost complete recovery of the angiogenic phenotype (80% of Foxp3(gfp) controls). A survey of lung gene expression of angiogenic (lipopolysaccharide-induced CXC chemokine [LIX], IL-6, IL-17) and angiostatic (IFN-γ, transforming growth factor-β, IL-10) cytokines showed Treg-dependent differences only in LIX (CXCL5) and IL-6. Protein confirmation demonstrated a significant reduction in LIX in Treg-deficient mice compared with controls 5 days after the onset of ischemia. Phenotyping other inflammatory cells in the lung by multicolor flow cytometry demonstrated a significantly reduced number of macrophages (major histocombatibility complex class II [MHCII](int), CD11C(+)) in Treg-deficient lungs compared with Treg-sufficient lungs. Treg cells are essential for maximal systemic angiogenesis after pulmonary ischemia. One likely mechanism responsible for the decrease in angiogenesis in Treg-depleted mice was the decline in the essential CXC chemokine, LIX.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Franco R
authors.initials: FR
authors.lastname: D'Alessio
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhong
authors.forename: John
authors.initials: J
authors.lastname: Jenkins
authors.forename: Aigul
authors.initials: A
authors.lastname: Moldobaeva
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wagner
mesh_terms: D019264:Adoptive Transfer; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D054365:Chemokine CXCL5 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D007511:Ischemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008168:Lung / Q000098:blood supply*; D008264:Macrophages / Q000276:immunology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D013997:Time Factors
chemical_list: D042501:Angiogenic Proteins; D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse
keywords: CXC chemokines; angiogenesis; ischemia; regulatory T cells