Abstract
BackgroundCD8+ T lymphocytes are critical mediators of neuroinflammatory diseases. Understanding the mechanisms that govern the function of this T cell population is crucial to better understanding central nervous system autoimmune disease pathology. We recently identified a novel population of highly cytotoxic c-Met-expressing CD8+ T lymphocytes and found that hepatocyte growth factor (HGF) limits effective murine cytotoxic T cell responses in cancer models. Here, we examined the role of c-Met-expressing CD8+ T cells by using a MOG35–55 T cell-mediated EAE model.MethodsMice were subcutaneously immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35–55 in complete Freund’s adjuvant (CFA). Peripheral and CNS inflammation was evaluated at peak disease and chronic phase, and c-Met expression by CD8 was evaluated by flow cytometry and immunofluorescence. Molecular, cellular, and killing function analysis were performed by real-time PCR, ELISA, flow cytometry, and killing assay.ResultsIn the present study, we observed that a fraction of murine effector CD8+ T cells expressed c-Met receptor (c-Met+CD8+) in an experimental autoimmune encephalitis (EAE) model. Phenotypic and functional analysis of c-Met+CD8+ T cells revealed that they recognize the encephalitogenic epitope myelin oligodendrocyte glycoprotein37–50. We demonstrated that this T cell population produces higher levels of interferon-γ and granzyme B ex vivo and that HGF directly restrains the cytolytic function of c-Met+CD8+ T cells in cell-mediated cytotoxicity reactionsConclusionsAltogether, our findings suggest that the HGF/c-Met pathway could be exploited to modulate CD8+ T cell-mediated neuroinflammation.
Highlights
The prevailing opinion is that multiple sclerosis (MS) is a CD4 T cell-mediated disease
We recently found that a fraction of murine cytotoxic lymphocytes (CTLs) expresses c-Met (c-Met+ Cytotoxic T lymphocytes (CTL))
We hypothesized that the c-Met signature could directly regulate CD8 effector functions in central nervous system (CNS) demyelination
Summary
The prevailing opinion is that multiple sclerosis (MS) is a CD4 T cell-mediated disease. The exact role of CD8+ T lymphocytes in autoimmune central nervous system (CNS) inflammation remains controversial, and some evidence supports both pathogenic and protective roles for these cells in MS and in experimental autoimmune encephalomyelitis (EAE). Human and mouse CD8+ T lymphocytes detected in the inflamed CNS compartment are predominantly CD62LCCR7- effector memory lymphocytes. CD8+ T lymphocytes are critical mediators of neuroinflammatory diseases. Understanding the mechanisms that govern the function of this T cell population is crucial to better understanding central nervous system autoimmune disease pathology. We recently identified a novel population of highly cytotoxic c-Met-expressing CD8+ T lymphocytes and found that hepatocyte growth factor (HGF) limits effective murine cytotoxic T cell responses in cancer models. We examined the role of c-Met-expressing CD8+ T cells by using a MOG35–55 T cell-mediated EAE model
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