title: Proangiogenic Function of T Cells in Corneal Transplantation.
abstract: Corneal neovascularization increases the risk of T cell-mediated allograft rejection. Here, we investigate whether T cells promote angiogenesis in transplantation.
  
  
  
  Conventional effector T cells were collected from draining lymph nodes of allogeneic or syngeneic corneal transplanted BALB/c mice. T cells were either cocultured with vascular endothelial cells (VECs) to assess VEC proliferation or used in a mixed lymphocyte reaction assay. Messenger RNA (mRNA) expression of vascular endothelial growth factor (VEGF)-A, -C, and VEGF receptor 2 (VEGF-R2) in VECs was assessed by real-time PCR. VEGF-A protein expression was determined by enzyme-linked immunosorbent assay. Flow cytometry was used to analyze VEGF-R2 expression in corneal CD31 cells, and VEGF-A and IFNγ expression in corneal CD4 T cells.
  
  
  
  Allogeneic T cells from high-risk (HR) grafted mice induced more VEC proliferation than those from syngeneic transplant recipients (P = 0.03). Vascular endothelial growth factor-A mRNA and protein expression were higher in T cells from draining lymph nodes (P = 0.03 and P = 0.04, respectively) and cornea (protein; P = 0.04) of HR compared with low-risk (LR) grafted hosts. Vascular endothelial growth factor-A, VEGF-C, and VEGF-R2 mRNA expression were increased in VECs when cocultured with T cells from HR transplants compared with LR transplants and naive mice. In addition, IFNγ blockade in T cell/VEC coculture increased VEC proliferation and VEGF-A protein expression, whereas blocking VEGF-A significantly reduced VEC proliferation (P = 0.04).
  
  
  
  Allogeneic T cells from corneal transplant hosts promote VEC proliferation, probably via VEGF-A signaling, whereas IFNγ shows an antiangiogenic effect. Our data suggest that T cells are critical mediators of angiogenesis in transplantation.
authors.affiliation: 1 Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Zazzo
authors.forename: Maryam
authors.initials: M
authors.lastname: Tahvildari
authors.forename: Brinda
authors.initials: B
authors.lastname: Subbarayal
authors.forename: Jia
authors.initials: J
authors.lastname: Yin
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Dohlman
authors.forename: Takenori
authors.initials: T
authors.lastname: Inomata
authors.forename: Alireza
authors.initials: A
authors.lastname: Mashaghi
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Chauhan
authors.forename: Reza
authors.initials: R
authors.lastname: Dana
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D018920:Coculture Techniques; D003315:Cornea / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism / Q000601:surgery*; D016510:Corneal Neovascularization / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016039:Corneal Transplantation / Q000009:adverse effects*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C467480:vascular endothelial growth factor A, mouse; C467483:vascular endothelial growth factor C, mouse; D007371:Interferon-gamma; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2