Increased Intrathecal Activity of Follicular Helper T Cells in Patients With Relapsing-Remitting Multiple Sclerosis

BACKGROUND AND OBJECTIVES: Follicular helper T (Tfh) cells play a critical role in protective immunity helping B cells produce antibodies against foreign pathogens and are likely implicated in the pathogenesis of various autoimmune diseases. The purpose of this study was to investigate the role of Tfh cells in the pathogenesis of multiple sclerosis (MS). METHODS: Using flow cytometry, we investigated phenotype, prevalence, and function of Tfh cells in blood and CSF from controls and patients with relapsing-remitting MS (RRMS) and primary progressive MS (PPMS). In addition, an in vitro blood-brain barrier coculture assay of primary human astrocytes and brain microvascular endothelial cells grown in a Boyden chamber was used to assess the migratory capacity of peripheral Tfh cells. RESULTS: This study identified 2 phenotypically and functionally distinct Tfh cell populations: CD25(−) Tfh cells (Tfh1-like) and CD25(int) Tfh cells (Tfh17-like). Whereas minor differences in Tfh cell populations were found in blood between patients with MS and controls, we observed an increased frequency of CD25(−) Tfh cells in CSF of patients with RRMS and PPMS and CD25(int) Tfh cells in patients with RRMS, compared with controls. Increasing frequencies of CSF CD25(−) Tfh cells and the CD25(−) Tfh/Tfr ratio scaled with increasing IgG index in patients with RRMS. Despite an increased prevalence of intrathecal Tfh cells in patients with MS, no difference in the migratory capacity of circulating Tfh cells was observed between controls and patients with MS. Instead, CSF concentrations of CXCL13 scaled with total counts of Tfh and Tfr cell subsets in the CSF. DISCUSSION: Our study indicates substantial changes in intrathecal Tfh dynamics, particularly in patients with RRMS, and suggests that the intrathecal inflammatory environment in patients with RRMS promotes recruitment of peripheral Tfh cells rather than the Tfh cells having an increased capacity to migrate to CNS.