ORCID Profile
0000-0001-6241-459X
Current Organisation
CNRS
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Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: Oxford University Press (OUP)
Date: 08-1999
Abstract: In contrast to most organs, the anatomy of the liver may allow naive CD8(+) T cells to make direct contact with liver parenchymal cells. We have previously shown, using a combination of TCR transgenic T cells specific for H-2 K(b) and hepatocytes expressing a transgenic H-2 K(b) molecule, that hepatocytes can induce antigen-specific activation and proliferation of naive CD8(+) T cells independently of CD28 co-stimulation. However, T cell activation by hepatocytes leads to premature T cell death and tolerance, both in vivo and in vitro. In this study, we investigated the mechanisms of T cell death induced by hepatocytes in vitro using primary hepatocytes to activate purified CD8(+) T cells. Neither Fas nor tumor necrosis factor receptor were involved, indicating that hepatocyte- induced death was distinct from activation-induced cell death. Before they started to ide, T cells activated by hepatocytes expressed lower levels of the bcl-x(L) survival gene and 30 times less IL-2 mRNA than CD8(+) cells activated by splenic antigen-presenting cells. Since CD28 co-stimulation increases both IL-2 and bcl-x(L) expression, this suggests that hepatocyte-activated T cells die by neglect because they fail to receive effective co-stimulatory signals. In agreement with this model, premature death promoted by hepatocytes could be prevented by cross-linking CD28. Survival after CD28 cross-linking correlated with increased IL-2 and bcl-x(L) expression, and sustained T cell proliferation, while cytotoxic T lymphocyte activity was prolonged as compared with cells stimulated without CD28 co-stimulation. This study confirms that high- affinity TCR transgenic antigen-specific CD8(+) T cells can be activated to proliferate and differentiate into cytotoxic effector cells. However, prolonged T cell survival and cytotoxicity required CD28 co-stimulation as well. To our knowledge, this is the first report suggesting that tolerance in the context of lack of CD28 co-stimulation can result from Fas-independent peripheral deletion rather than from anergy.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2013
DOI: 10.1038/NCB2774
Abstract: Dysfunctional telomeres suppress tumour progression by activating cell-intrinsic programs that lead to growth arrest. Increased levels of TRF2, a key factor in telomere protection, are observed in various human malignancies and contribute to oncogenesis. We demonstrate here that a high level of TRF2 in tumour cells decreased their ability to recruit and activate natural killer (NK) cells. Conversely, a reduced dose of TRF2 enabled tumour cells to be more easily eliminated by NK cells. Consistent with these results, a progressive upregulation of TRF2 correlated with decreased NK cell density during the early development of human colon cancer. By screening for TRF2-bound genes, we found that HS3ST4--a gene encoding for the heparan sulphate (glucosamine) 3-O-sulphotransferase 4--was regulated by TRF2 and inhibited the recruitment of NK cells in an epistatic relationship with TRF2. Overall, these results reveal a TRF2-dependent pathway that is tumour-cell extrinsic and regulates NK cell immunity.
Publisher: The American Association of Immunologists
Date: 10-2013
Abstract: The inflammasome is a signaling platform that is central to the innate immune responses to bacterial infections. Francisella tularensis is a bacterium replicating within the host cytosol. During F. tularensis subspecies novicida infection, AIM2, an inflammasome receptor sensing cytosolic DNA, activates caspase-1 in an ASC-dependent manner, leading to both pyroptosis and release of the proinflammatory cytokines IL-1β and IL-18. Activation of this canonical inflammasome pathway is key to limit F. novicida infection. In this study, by comparing the immune responses of AIM2 knockout (KO), ASCKO, and Casp1KO mice in response to F. novicida infection, we observed that IFN-γ levels in the serum of Casp1KO mice were much higher than the levels observed in AIM2KO and ASCKO mice. This difference in IFN-γ production was due to a large production of IFN-γ by NK cells in Casp1KO mice that was not observed in ASCKO mice. The deficit in IFN-γ production observed in ASCKO mice was not due to a reduced Dock2 expression or to an intrinsic defect of ASCKO NK cells. We demonstrate that in infected Casp1KO mice, IFN-γ production is due to an ASC-dependent caspase-1–independent pathway generating IL-18. Furthermore, we present in vitro data suggesting that the recently described AIM2/ASC/caspase-8 noncanonical pathway is responsible for the caspase-1–independent IL-18 releasing activity. To our knowledge, this study is the first in vivo evidence of an alternative pathway able to generate in a caspase-1–independent pathway bioactive IL-18 to boost the production of IFN-γ, a cytokine critical for the host antibacterial response.
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