GSE211358
Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
B cell depletion in patients with relapsing remitting multiple sclerosis (RRMS) markedly prevents new MRI 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 memory B cells from patients with MS and healthy age-matched controls stimulated with CD40L and IL-21, 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 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 TIGIT/CD155 axis. Finally, CCR6+ cTfh cells were significantly increased in MS and their frequency was inversely correlated with that of TIGIT+ B cells. Together, these data suggest that the dysregulation of negative feedback loops between TIGIT+ memory B cells and cTfh cells in MS drive the activated immune system in the disease. Overall design: memory B cell profiles of patients with multiple sclerosis and healthy donors in multiple conditions (A) treated with CD40L+IL-21, B) CD40L or CD40L+IL-4 treated, C) TIGIT+, IL-10+ B cells )