Although the primary event(s) triggering relapsing-remitting multiple sclerosis (RRMS) are still under investigation, disease maintenance requires a recurrent infiltration of immune cells from the periphery to the central nervous system. There, immune cells interplay with cells from local and peripheral origins dictate their functions and phenotype, polarizing them toward a pathological or a suppressive subset. To adapt energy demand to their new roles, cell metabolism have to be shaped accordingly stressing the need to consider it in association with cell phenotype. In this study we described immune cells polarization within the Cerebro Spinal Fluid (CSF), their interplay with other infiltrating subsets and their potentially associated metabolic switch. Immune cells from CSF and paired blood (n=5) of RRMS patients were sampled at diagnosis and used for scRNAseq analysis. Gene expression profile, cells interactome, clonal amplification and metabolome were assessed and compared between CSF and blood. Immune cells recruitment to the CSF was associated to an upregulation of activation markers at their surface and to a strong shift of their metabolism toward higher cholesterol biosynthesis. In accordance, enrichment in pro-inflammatory cell populations comprising antigen presenting monocytic cells and B cells as well as GzmK CD4 T cells was observed within the CSF. Increased frequency of these T and B subsets was partly explained through their clonal amplification which was found exclusive to the CSF. Finally, interactome analysis demonstrated differential crosstalk properties among infiltrating cells with Tbet B cells specific expression of CD22, while CCL5 expression was mostly restricted to GzmK CD4 T cells. Altogether, these results highlighted that at diagnosis, RRMS patient’s CSF is already enriched with pro-inflammatory cells which had experienced a metabolic switch. Among these subsets, B cells and GzmK CD4 T cells demonstrated clonal expansion and peculiar interacting properties illustrative of their central role in disease course and maintenance.