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-gamma, 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 naive 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.