c-Met is expressed by highly autoreactive encephalitogenic CD8+ cells

Abstract

Background: 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. Here, we examined the role of c-Met-expressing CD8 + T cells by using a MOG 35-55 T cell-mediated EAE model. Methods: Mice 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. Results: In 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 glycoprotein 37-50. 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 reactions Conclusions: Altogether, our findings suggest that the HGF/c-Met pathway could be exploited to modulate CD8 + T cell-mediated neuroinflammation.

c-Met enforces proinflammatory and migratory features of human activated CD4+ T cells

“…Recently, we found that a fraction of murine cytotoxic CD8 + T lymphocytes (CTLs) expressed c-Met (c-Met + CTLs). We also demonstrated the presence of c-Met + CTLs in mouse tumors [ 5 ] and central nervous system (CNS) autoimmunity models [ 6 ]. Interestingly, c-Met + CTL populations arise only under conditions caused by a pathological microenvironment.…”

A randomised, double-blind, placebo-controlled, multicentre clinical trial of AZD1656 in diabetic patients hospitalised with COVID-19: The ARCADIA Trial - implications for therapeutic immune modulation

“…Differences were also observed in the adaptive immune system, particularly in activated (cMet+) Tcells. 11,12 Increases in Th1-IFN cMet+ and Th1-TNF cMet+ were observed in the AZD1656 group at multiple timepoints but not the Placebo Group and there was a difference between groups for Th1-IFN cMet+ at one timepoint (SDD) (p=0¢0049). Differences were observed in the cells involved in the antibody response: Th2 cells decreased in the Placebo group at SDD (p=0¢ 035), leading to a difference between groups at SDD (p=0¢038).…”

Targeting HGF/c-Met Axis Decreases Circulating Regulatory T Cells Accumulation in Gastric Cancer Patients

“…This is in accordance with previous reports showing no expression of c-Met on naïve T cells, or on circulating CD4 + T cells from multiple sclerosis patients [ 24 ]. Only subsets of highly autoreactive encephalitogenic CD8 + T cells and of CD4 + memory T cells which preferentially recirculate in the heart have been reported to express c-Met in mice [ 25 , 26 ]. On the other hand, we found that c-Met was present on circulating monocytes from GC patients.…”