CD4+c-Met+Itgα4+ T cell subset promotes murine neuroinflammation
ABSTRACT
c-Met, a tyrosine kinase receptor, is the unique receptor for hepatocyte growth factor (HGF). The HGF/cMet axis is reported to modulate cell migration, maturation, cytokine production, and antigen presentation. In this article, published in Journal of Neuroinflammation, the groupe of GCIR member Professor Patrice Lalive report that CD4+c-Met+ T cells are detected at increased levels in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). c-Met expression by CD4+ T cells was analyzed by flow cytometry and by immunohistochemistry from mice and human PBMCs and the in vivo role of CD4+c-Met+ T cells was assessed in EAE.
CD4+c-Met+ T cells found in the CNS during EAE peak disease are characterized by a pro-inflammatory phenotype skewed towards a Th1 and Th17 polarization, with enhanced adhesion and transmigration capacities correlating with increased expression of integrin α4 (Itgα4). The adoptive transfer of Itgα4-expressing CD4+Vα3.2+c-Met+ T cells induces increased disease severity compared to CD4+Vα3.2+c-Met− T cells. Finally, CD4+c-Met+ T cells are detected in the brain of MS patients, as well as in the blood with a higher level of Itgα4. These results highlight c-Met as an immune marker of highly pathogenic pro-inflammatory and pro-migratory CD4+ T lymphocytes associated with neuroinflammation.
This work is supported by the Swiss National Science Foundation.
IMPLICATIONS
Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system (CNS). Numerous immune cells have been detected in MS lesions, including CD4+ and CD8+ T-lymphocytes, suggesting their involvement in MS disease development.
This study, first authored by Dr Mahdia Benkhoucha, reports that a significant proportion of activated CD4+ T cells in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, express the tyrosine kinase c-Met receptor, while this expression remains minimal in immature CD4+ T cells. CD4+c-Met+ T cells were also detected in the brain of MS patients. The results of the study suggest a correlation of CD4+c-Met+ T cells with pathological systemic inflammation, shedding light on the mechanisms of MS pathogenesis. Further research on this molecule is needed in order to develop new therapies to treat MS.