title: The neurotrophic hepatocyte growth factor attenuates CD8+ cytotoxic T-lymphocyte activity.
abstract: 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.
authors.forename: Mahdia
authors.initials: M
authors.lastname: Benkhoucha
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molnarfi
authors.forename: Gregory
authors.initials: G
authors.lastname: Schneiter
authors.forename: Paul R
authors.initials: PR
authors.lastname: Walker
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. patrice.lalive@hcuge.ch.
authors.forename: Patrice H
authors.initials: PH
authors.lastname: Lalive
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D017228:Hepatocyte Growth Factor / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D017228:Hepatocyte Growth Factor