Pro-Inflammatory c-Met⁺ CD4 T Cells in Multiple Sclerosis

Hepatocyte growth factor (HGF) binds exclusively the c-Met surface receptor, and the HGF/c-Met axis regulates T cell function in autoimmune diseases. We analyzed c-Met expression on human CD4 T cells in the blood and cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) versus non-inflammatory neurological disease (NIND), to better understand the role of CD4 T cells in MS.

We recruited 34 untreated MS patients (age 28-44 years) and 13 NIND (age 34-51 years) who underwent paired blood and CSF sampling at the time of diagnosis work-up. Phenotypic and functional CD4 T cells characterization was determined by flow cytometry and bulk RNA sequencing. Adhesion and transmigration capacities were studied to further characterize the function of c-Met⁺ CD4 T cells.

c-Met⁺ memory CD4 T cells were detected at higher levels in both blood (median of 1.98%) and CSF (5.88%) in MS compared to NIND (0.37% and 0.68%, respectively) (p < 0.0001). Ex vivo c-Met⁺ CD4 T cells exhibited higher levels of GM-CSF, interleukin (IL)-17, interferon (IFN)- $\gamma$ , and double positive IL-17⁺IFN- $\gamma$ ⁺ expression, compared with c-Met^- CD4 T cells. c-Met⁺ CD4 T cells expressed increased levels of integrins-Itgα4β1 (VLA-4) and ItgαLβ2 (LFA-1)-compared with c-Met^- CD4 T cells. Anti-Itgα4 (natalizumab) and anti-ItgαLβ2 (odulimomab) inhibited CD4 T cell transmigration with predominant inhibition of CD4 T cells expressing c-Met.

These results emphasize c-Met as an immune marker of highly pro-inflammatory and migratory CD4 T lymphocytes in both the periphery and central nervous system of MS patients. ANN NEUROL 2026;99:261-273.