Here, we analyzed c-Met expression on human CD4⁺ T cells from multiple sclerosis (MS) patients versus patients with non inflammatory neurological disease (NIND), with the ultimate goal to better understand the role of this new cells population in MS disease.

Tyrosine kinase receptor c-Met is the unique receptor for hepatocyte growth factor (HGF). The HGF/c-Met axis is reported to modulate cell migration, cytokine production, and antigen presentation.

Cells were isolated from blood and CSF samples of MS and NIND patients from December 2020 to December 2022 at Geneva University Hospital. Cell number, cell viability, and phenotypic characterization were determined by RNA sequencing (bulk) and flow cytometry. Adhesion and transmigration capacity were studied to further characterize the function of activated c-Met⁺CD4⁺ T cells.

c-Met⁺CD4⁺ T cells are detected at higher levels in both blood and CSF of MS patients compared to NIND with a blood to CSF gradient. The phenotype of CD4⁺c-Met⁺ T cells is oriented toward Th17.1 polarization with a predominance of central memory and effector memory activity profiles. c-Met⁺ CD4⁺ T cells have increased proinflammatory activity, showing higher intracellular levels of IL-17⁺ and IL-17⁺IFNγ⁺ compared with c-Met^-CD4⁺ T cells. c-Met⁺CD4⁺ T cells showed increased transmigration capacity correlated with increased expression of integrins (Itgα4, Itgβ1, Itgβ7, Itgα4β1, Itgα4β7, ItgαLβ2) in transcriptomic (bulk mRNA sequencing) and surface protein (flow cytometry) analyses compared with c-Met^-CD4⁺ T cells. Anti-Itgα4 (natalizumab) and anti-ItgαLβ2 (odulimomab) inhibit CD4⁺ T cell transmigration with predominant inhibition of c-Met⁺CD4⁺ T cells compared with c-Met^-CD4⁺ T cells.

These results emphasize c-Met as an immune marker of highly pro^-inflammatory and pro^-migratory CD4⁺ T lymphocytes in MS.