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Transforming growth factor beta expression by human vascular cells inhibits interferon gamma production and arterial media injury by alloreactive memory T cells.

ABSTRACT: Arteriosclerosis is characterized by the local activation of effector T cells leading to production of proinflammatory cytokines, such as IFN (interferon)-? and IL-17, within the vessel wall. Conversely, the production of antiinflammatory cytokines, for example, TGF-?, by regulatory lymphocytes is known to inhibit both the differentiation of naïve T cells into effector T cells and the development of arteriosclerosis in murine models. We investigated the role of TGF-? on the alloreactivity of human effector memory T cells (Tem). Quiescent vascular cells, but not Tem, expressed TGF-?. Blockade of TGF-? activity in cocultures of CD4(+) Tem with allogeneic endothelial cells significantly increased IFN-?, but not IL-17, secretion. Additionally, serologic neutralization of TGF-? in immunodeficient mouse hosts of human coronary artery grafts into which allogeneic human T cells were adoptively transferred resulted in heavier medial infiltration by Tem, greater loss of medial smooth muscle cells and increased IFN-? production within the grafts without significantly reducing either intimal injury or IL-17 production. Protective effects of TGF-? may be limited by fewer TGF-?-expressing vascular cells within the intimal compartment, by a reduction in the expression of TGF-? by vascular cells in rejecting grafts, or possibly to less effective suppression of Tem than naïve T cells.

SUBMITTER: Lebastchi AH

PROVIDER: S-EPMC3203343 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Transforming growth factor beta expression by human vascular cells inhibits interferon gamma production and arterial media injury by alloreactive memory T cells.

Lebastchi A H AH Khan S F SF Qin L L Li W W Zhou J J Hibino N N Yi T T Rao D A DA Pober J S JS Tellides G G

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20110803 11

Arteriosclerosis is characterized by the local activation of effector T cells leading to production of proinflammatory cytokines, such as IFN (interferon)-γ and IL-17, within the vessel wall. Conversely, the production of antiinflammatory cytokines, for example, TGF-β, by regulatory lymphocytes is known to inhibit both the differentiation of naïve T cells into effector T cells and the development of arteriosclerosis in murine models. We investigated the role of TGF-β on the alloreactivity of hum ...[more]

PMID: 21812925

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Project description:BackgroundDespite improvements in disease diagnosis, treatment, and prognosis, breast cancer is still a leading cause of cancer death for women. Compelling evidence suggests that targeting cancer stem cells (CSCs) have a crucial impact on overcoming the current shortcomings of chemotherapy and radiotherapy. In the present study, we aimed to study the effects of T cells and a critical anti-tumor cytokine, interferon-gamma (IFN-γ), on breast cancer stem cells.MethodsBALB/c mice and BALB/c nude mice were subcutaneously injected with 4T1 tumor cells. Tumor growth and pulmonary metastasis were assessed. ALDEFLOUR™ assays were performed to identify aldehyde dehydrogenasebright (ALDHbr) tumor cells. ALDHbr cells as well as T cells from tumor-bearing BALB/c mice were analyzed using flow cytometry. The effects of CD8+ T cells on ALDHbr tumor cells were assessed in vitro and in vivo. The expression profiles of ALDHbr and ALDHdim 4T1 tumor cells were determined. The levels of plasma IFN-γ were measured by enzyme-linked immunosorbent assay, and their associations with the percentages of ALDHbr tumor cells were evaluated. The effects of IFN-γ on ALDH expression and the malignancy of 4T1 tumor cells were analyzed in vitro.ResultsThere were fewer metastatic nodules in tumor-bearing BALB/c mice than those in tumor-bearing BALB/c nude mice (25.40 vs. 54.67, P < 0.050). CD8+ T cells decreased the percentages of ALDHbr 4T1 tumor cells in vitro (control vs. effector to target ratio of 1:1, 10.15% vs. 5.76%, P < 0.050) and in vivo (control vs. CD8+ T cell depletion, 10.15% vs. 21.75%, P < 0.001). The functions of upregulated genes in ALDHbr 4T1 tumor cells were enriched in the pathway of response to IFN-γ. The levels of plasma IFN-γ decreased gradually in tumor-bearing BALB/c mice, while the percentages of ALDHbr tumor cells in primary tumors increased. IFN-γ at a concentration of 26.68 ng/mL decreased the percentages of ALDHbr 4T1 tumor cells (22.88% vs. 9.88%, P < 0.050) and the protein levels of aldehyde dehydrogenase 1 family member A1 in 4T1 tumor cells (0.86 vs. 0.49, P < 0.050) and inhibited the abilities of sphere formation (sphere diameter <200 μm, 159.50 vs. 72.0; ≥200 μm, 127.0 vs. 59.0; both P < 0.050) and invasion (89.67 vs. 67.67, P < 0.001) of 4T1 tumor cells.ConclusionCD8+ T cells and IFN-γ decreased CSC numbers in a 4T1 mouse model of breast cancer. The application of IFN-γ may be a potential strategy for reducing CSCs in breast cancer.

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Transforming growth factor beta expression by human vascular cells inhibits interferon gamma production and arterial media injury by alloreactive memory T cells.

Publications

Transforming growth factor beta expression by human vascular cells inhibits interferon gamma production and arterial media injury by alloreactive memory T cells.

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