RESUMO
BACKGROUND: Corneal neovascularization increases the risk of T cell-mediated allograft rejection. Here, we investigate whether T cells promote angiogenesis in transplantation. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Córnea/irrigação sanguínea , Córnea/cirurgia , Neovascularização da Córnea/etiologia , Transplante de Córnea/efeitos adversos , Neovascularização Patológica , Animais , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , Proliferação de Células , Técnicas de Cocultura , Córnea/imunologia , Córnea/metabolismo , Neovascularização da Córnea/imunologia , Neovascularização da Córnea/metabolismo , Neovascularização da Córnea/patologia , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Interferon gama/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transdução de Sinais , Transplante Homólogo , Transplante Isogênico , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Accumulating evidence shows that IL-17 is critically involved in diverse autoimmune diseases. However, its effect on the induction and progression of the humoral immune response is not fully understood. Using a preclinical model of IL-17-mediated dry eye disease, we demonstrate that upon encountering both the BCR and a secondary T cell signal, IL-17 can enhance B cell proliferation and germinal center formation in dry eye disease mice, suggesting that a stable Ag-dependent T-B cell interaction is required. Additionally, IL-17 also promotes the differentiation of B cells into isotype-switched B cells and plasma cells. Furthermore, we show that Th17 cells are more effective than Th1 cells to provide B cell help. Reduced B cell response correlates with significant reduction in clinical disease after in vivo IL-17A neutralization. In conclusion, our findings demonstrate a new role of IL-17 in promoting autoimmunity in part through directly enhancing B cell proliferation, differentiation, and plasma cell generation.
