c-Met is a transmembrane tyrosine kinase receptor for hepatocyte growth factor (HGF) involved in cell survival, cell growth and regeneration. HGF/c-Met axis modulates several inflammatory-mediated diseases, including in experimental autoimmune encephalomyelitis (EAE), by acting on a wide variety of cells. We demonstrated the multiple anti-inflammatory effects of HGF, such as tolerizing DCs and inducing Treg response. We recently showed that HGF modulates cell function ex vivo in myelin oligodendrocyte glycoprotein peptide (MOG)35-55-induced EAE. Indeed,
we demonstrated that c-Met-expressing CD8+ T cell population produces higher levels of interferon-γ and granzyme B ex vivo and that HGF directly restrains the cytolytic function of this T cells population in cell-mediated cytotoxicity reactions. These findings suggest that the HGF/c-Met pathway could be exploited to modulate T cell-mediated neuroinflammation in EAE and MS.
Our aim is to characterize the novel population of c-Met-expressing CD4+ T cells and to study their capacity to drive antigen-specific autoimmune diseases. We also examined the capacity of HGF to modulate c-Met-expressing CD4+ T cell function.
Mice were subcutaneously immunized with MOG35–55 in complete Freund’s adjuvant (CFA). Peripheral and CNS inflammation was evaluated at peak disease and chronic phase, c-Met expression by CD4+ T cells was evaluated by flow cytometry and immunofluorescence. Molecular and cellular function analysis were performed by molecular biology technics, multiplex and flow cytometry.
We found that a subpopulation of effector CD4+ T cells expresses c-Met in EAE. These cells were transcriptomically distinct from conventional CD4+cMet- T cells, poised to migrate to inflammation sites and expressing high expression of VLA-4 integrin, chemokine receptors and homing molecules. In addition, our results offer a phenotypic and functional characterization of this new population ex vivo and in vitro and how we could consider them as the main population of pathogenic T cells driving EAE.
Our findings suggest that c-Met expression by CD4+ T cells confers specific pro-inflammatory and migratory properties in MOG35–55-induced EAE.