B cell depletion attenuates CD27 signaling of T helper cells in multiple sclerosis

Abstract Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Traditionally, MS was held to be a T-cell mediated disease, but accumulating evidence during the last decade also highlighted the crucial importance of B cells for the disease progression. Particularly, B cell depleting therapies (BCDTs), have demonstrated striking efficacy in suppressing inflammatory disease activity in relapsing-remitting MS. However, a detailed understanding of the role of B cells in the pathogenesis of MS is still lacking, and by extension also the mechanism of action of BCDTs. In this longitudinal multi-center study, we investigated the impact of BCDTs on the immune landscape in MS patients using high-dimensional single-cell immunophenotyping (cytometry by time-of-flight; CyTOF). Algorithm-guided analyses revealed phenotypic changes in the newly reconstituted B cell compartment after BCDT, as well as a marked specific reduction of circulating T follicular helper (Tfh) cells with a concomitant upregulation of CD27 surface expression in memory T helper cells and Tfh cells. These findings indicate a costimulatory mechanism in the CD27/CD70 signaling pathway, through which B cells sustain the activation of pathogenic T cells. Disrupting the CD27/CD70 signaling axis via BCDTs provides a potential explanation for its clinical efficacy. One Sentence Summary B cell depletion contracts follicular T helper cells, displaces memory-to-naïve ratio and impairs CD27 signaling in T helper cells.