The neurotrophic hepatocyte growth factor attenuates CD8+ cytotoxic T-lymphocyte activity

Background: accumulating evidence suggests a deleterious role for cd8+ t cells in multiple sclerosis (ms) pathogenesis. we have recently reported that hepatocyte growth factor (hgf),a potent neuroprotective factor,limits cd4+ t cell-mediated autoimmune neuroinflammation by promoting tolerogenic dendritic cells (dcs) and subsequently regulatory t cells. whether hgf modulates cell-mediated immunity driven by mhc class i-restricted cd8+ t cells remains to be determined.methods: here we examined whether hgf regulates antigen-specific cd8+ t cell responses using an established model of murine cytotoxic t lymphocyte (ctl)-mediated killing.results: we found that hgf treatment of gp100-pulsed dcs reduced the activation of gp100-specific t cell receptor (pmel-1) cd8+ t cells and subsequent mhc class i-restricted ctl-mediated cytolysis of gp100-pulsed target cells. the levels of perforin,granzyme b,ifn-γ,and the degranulation marker cd107a as well as fas ligand were decreased among cd8+ t cells,suggestive of a dual inhibitory effect of hgf on the perforin/granzyme b- and fas-based lytic pathways in cell-mediated cytotoxicity. treatment of cd8+ t cells with concanamycin a,a potent inhibitor of the perforin-mediated cytotoxic pathway,abrogated ctl cytotoxicity indicating that blockade of the perforin-dependent killing is a major mechanism by which hgf diminished cytolysis of gp100-pulsed target cells. moreover,hgf suppressed the generation of effector memory ctls.conclusions: our findings indicate that hgf treatment limits both the generation and activity of effector ctl from naïve cd8+ t cells. complementary to its impact on cd4+ t-cell cns autoimmunity and myelin repair,our findings further suggest that hgf treatment could be exploited to control cd8+ t-cell-mediated,mhc i-restricted autoimmune dysfunctions such as ms. © 2013 benkhoucha et al.; licensee biomed central ltd.