Journal Article

Lung Angiogenesis Requires CD4 + Forkhead Homeobox Protein-3 + Regulatory T Cells

D’Alessio, Franco R., Moldobaeva, Aigul, Wagner, Elizabeth M., Zhong, Qiong, Jenkins, John

2015

Overview

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; Foxp3DTR), we unexpectedly found that Foxp3+ Treg depletion led to markedly reduced lung angiogenesis (90% reduction from Foxp3gfp 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 Foxp3gfp 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.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Adoptive Transfer / Angiogenesis / Angiogenic Proteins - genetics / Angiogenic Proteins - metabolism / Animals / CD11c antigen / CD25 antigen / CD4 antigen / CD45 antigen / Chemokine CXCL5 - genetics / Chemokine CXCL5 - metabolism / Chemokines / CXC chemokines / Diphtheria / Diphtheria toxin / Disease Models, Animal / Flow cytometry / Forkhead protein / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - metabolism / Foxp3 protein / Gene expression / Gene Expression Regulation / Homeobox / Immunoregulation / Interleukin 6 / Ischemia / Ischemia - genetics / Ischemia - immunology / Ischemia - metabolism / Ischemia - physiopathology / Lipopolysaccharides / Lung - blood supply / Lungs / Lymphocytes T / Macrophages / Macrophages - immunology / Mice, Inbred C57BL / Mice, Transgenic / Neovascularization, Physiologic / Original Research / Phenotype / Phenotypes / Proteins / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - metabolism / T-Lymphocytes, Regulatory - transplantation / Time Factors / Transgenic mice / Vascularization / γ-Interferon