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Introduction Relapsing-remitting multiple sclerosis (RRMS) is a genetically mediated autoimmune disease mediated by mye[Lin.sup.-]reactive T cells attacking the CNS (1-3) and is characterized by inflammatory lesions predominantly in the white [...], B cell depletion in patients with relapsing-remitting multiple sclerosis (RRMS) markedly prevents new MRI-detected lesions and disease activity, suggesting the hypothesis that altered B cell function leads to the activation of T cells driving disease pathogenesis. Here, we performed comprehensive analyses of CD40 ligand- (CD40L-) and IL-21-stimulated memory B cells from patients with MS and healthy age-matched controls, modeling the help of follicular helper T cells (Tfh cells), and found a differential gene expression signature in multiple B cell pathways. Most striking was the impaired TIGIT expression on MS-derived B cells mediated by dysregulation of the transcription factor TCF4. Activated circulating Tfh cells (cTfh cells) expressed CD155, the ligand of TIGIT, and TIGIT on B cells revealed their capacity to suppress the proliferation of IL-17- producing cTfh cells via the TIGIT/CD155 axis. Finally, [CCR6.sup.+] cTfh cells were significantly increased in patients with MS, and their frequency was inversely correlated with that of [TIGIT.sup.+] B cells. Together, these data suggest that the dysregulation of negative feedback loops between [TIGIT.sup.+] memory B cells and cTfh cells in MS drives the activated immune system in this disease.