T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis
Ivan Jelčić, Reza Naghavian, Imran Fanaswala, Will Macnair, Cinzia Esposito, Daniela Calini, Yanan Han, Zoe Marti, Catarina Raposo, Jacobo Sarabia del Castillo, Pietro Oldrati, Daniel Erny, Veronika Kana, Galina Yurevna Zheleznyakova, Faiez Al Nimer, Björn Tackenberg, Ina Reichen, Mohsen Khademi, Fredrik Piehl, Mark D. Robinson, Ilijas Jelčić, Mireia Sospedra, Lucas Pelkmans, Dheeraj Malhotra, Richard Reynolds, Maja Jagodic, Roland Martinꝉ
Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Self-peptide-dependent autoproliferation (AP) of B and T cells is a key mechanism in MS. Here, we show that pro-inflammatory B-T cell-enriched cell clusters (BTECs) form during AP and mirror features of a germinal center reaction. T-bet+CXCR3+ B cells are the main cell subset amplifying and sustaining their counterpart Th1 cells via interferon (IFN)-γ and are present in highly inflamed meningeal tissue. The underlying B cell activation signature is reflected by epigenetic modifications and receptor-ligand interactions with self-reactive T cells. AP+ CXCR3+ B cells show marked clonal evolution from memory to somatically hypermutated plasmablasts and upregulation of IFN-γ-related genes. Our data underscore a key role of T-bet+CXCR3+ B cells in the pathogenesis of MS in both the peripheral immune system and the CNS compartment, and thus they appear to be involved in both early relapsing-remitting disease and the chronic stage. • Autoproliferation (AP) leads to germinal center-like B-T cell clusters in multiple sclerosis • T-bet+CXCR3+ B cells are strongly enriched in AP and develop into plasmablasts • AP+ CXCR3+ B cells potentiate Th1 responses and form an inflammatory circuit • They are associated with CSF cell counts and spinal cord lesions and found in inflamed meninges Memory B cells activate brain-homing autoreactive T cells in multiple sclerosis. Here, Jelcic et al. demonstrate that self-reactive B and T cells interact within inflammatory B-T cell clusters. We identify T-bet+CXCR3+ B cells to be the main driver in this inflammatory circuit through IFN-γ in both the periphery and inflamed meninges.