| Project Detail |
1. SUMMARY 1.1 BackgroundCD4+ T cells play a critical role in regulating human health by orchestrating the actions of the immune system against infections or cancer. In contrast, improper functioning of CD4+ T cells may be associated with autoimmune diseases, such as multiple sclerosis (MS). Our data indicate that T lymphocytes expressing hepatocyte growth factor (HGF) receptor (c-Met) is associated with a pro-inflammatory phenotype in chronic inflammation. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we have demonstrated that HGF indirectly attenuates encephalitogenic CD4+ T cell function via the induction of tolerogenic dendritic cells (DCs) (1-3). In models of murine cytotoxic CD8+ T lymphocyte (CTL)-mediated killing, we showed that HGF reduces the cytotoxic properties of CTLs via attenuation of DC functions (4-6). More recently, we demonstrated the presence of human c-Met-expressing CD4+ T cells upon T cell receptor (TCR) triggering. Phenotypic and functional analyses of CD4+c-Met+ T cells have revealed an enhanced pro-inflammatory and pro-migratory phenotype skewed toward IL-17-producing T helper cell. In addition, for the first time, we detected CD4+c-Met+ T cells in peripheral blood mononuclear cells (PBMCs) (7) and in the cerebrospinal fluid (CSF) (Figure 4, unpublished data) from MS patients. Finally, we have highlighted c-Met as both an immune marker of highly pathogenic pro-inflammatory and pro-migratory CD4+ T lymphocytes in a model of neuroinflammation (8). Collectively, our results suggest that the HGF/c-Met pathway could play a key role in the pathogenesis of MS. 1.2 Working hypothesis and experimental designWe hypothesize that signals induced by the HGF/c-Met axis directly modulate the functions of T lymphocytes in both EAE and MS patients. We propose to study the intracellular mechanisms implicated in the development of pro-inflammatory CD4+c-Met+ T cells during neuroinflammation. In addition, we will explore the immunomodulatory potential of HGF and c-Met blocking molecules (capmatinib and anti-c-Met antibodies) in EAE to better understand the function of HGF/c-Met signaling pathway. Moreover, characterizing CD4+c-Met+ T cell populations in the circulation and in the CSF of patients with MS, will allow us to confirm our hypothesis that this pro-inflammatory c-Met-expressing T cell population is differentialy regulated in MS patients compared to controls. Finally, we assume that c-Met-expressing innate lymphocyte cells - mirror of adaptive T helper cells - have also a role in neuroinflammation. 1.3 Specific AimsAim 1: Study the modulation of c-Met intracellular signaling pathway on CD4+ T cell functions in EAE Aim 2: Characterize c-Met-expressing T cells in PBMCs and cerebrospinal fluid (CSF) from MS patientsAim 3: Investigate c-Met expression on innate lymphoid cells from MS patients1.4 Expected value of the proposed projectThis project is a unique chance to further explore the potential relevance of the HGF/c-Met axis in regulating neuroinflammation mediated by T cells, such as MS. We propose for the first time, a detailed mechanistic study of the HGF/c-Met signaling pathway on CD4+ T lymphocytes in EAE and MS. We will also test whether the modulation of HGF/c-Met ameliorates disease outcomes in EAE. If confirmed, this approach could be considered for a clinical trial in MS on an accelerated basis, since this type of therapy (c-Met modulation) is already used in human oncology. |
