find protocol Altogether, these results indicate that HGF acts directly on DCs by reducing their ability to both generate and prime antigen specific CD8 T cell responses. Discussion HGF is a multifunctional cytokine that Inhibitors,Modulators,Libraries blunts inflamma tion in a variety of inflammatory T cell mediated Inhibitors,Modulators,Libraries disease models, suggesting that HGF suppresses a common in flammatory process. In MOG induced EAE, a common model of MS primarily mediated by encephalitogenic Inhibitors,Modulators,Libraries CD4 T cell responses and characterized by demyelin ation and axonal loss, we have previously demon strated that overexpression of neuronal HGF attenuated Inhibitors,Modulators,Libraries disease progression in part via anti inflammatory signals. Using this MS model, we established that HGF ex erts an anti inflammatory effect through the generation of tolerogenic DCs and the subsequent suppression of autoreactive peripheral Th1 and Th17 cells, leading to reduced CD4 T cell mediated CNS injury.

Whether HGF modulates cell mediated immunity driven by MHC class I restricted CD8 T cells remained unknown. In addition Inhibitors,Modulators,Libraries to pathogenic CD4 T cells, multiple ob servations support the idea that CD8 T cells are in volved in pathogenesis of CNS autoimmunity, as active contributors to the development of neuroinflammation. In MS, CD8 T cells outnumber by far CD4 T cells in both acute and chronic inflammatory lesions. In addition, while CD4 T cells show a primarily perivascu lar distribution, CD8 T cells can be detected in the par enchyma. Although normally poorly expressed, MHC class I molecules are highly expressed within the MS lesion on astrocytes, oligodendrocytes, and neurons, suggesting that CD8 T cells could be directly engaging these cell types.

Using an established selleck inhibitor model of murine CTL mediated killing we have here examined whether HGF could regulate autoaggressive, cytotoxic CD8 T cell responses. In this study, we found that HGF treatment of DCs reduced the generation and functions of cytotoxic ef fector CD8 T lymphocytes and subsequent MHC class I restricted CTL mediated cytolysis of target cells. The development of na ve cytotoxic CD8 T cells into CTLs requires specific recognition of antigen MHC class I complexes on professional APCs in conjunction with co stimulatory signals. Secondary recognition of antigen MHC class I complexes on a target cell by a CTL leads to the death of the target cell. Our findings indicate that HGF treatment interfered with the development of autoagressive CTLs and not their capacity to recognize their target cells. In particular, we found that HGF treat ment increased the levels of the inhibitory counter receptor CTLA4 molecules expressed on CD8 T cells but did not affect the expression of the CD3 molecules.