Memory B Cells Activate Brain-Homing, Autoreactive CD4 ⁺ T Cells in Multiple Sclerosis

Summary

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4 ⁺ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.

Graphical Abstract

Highlights

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  Autoproliferation of CD4 ⁺ T cells and B cells is involved in multiple sclerosis

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  The main genetic factor of MS, HLA-DR15, plays a central role in autoproliferation

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  Memory B cells drive autoproliferation of Th1 brain-homing CD4 ⁺ T cells

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  Autoproliferating T cells recognize antigens expressed in B cells and brain lesions

Abstract

Memory B cells drive proliferation of self-reactive brain-homing CD4 ⁺ T cells, which recognize autoantigens expressed in B cells and in brain lesions with target potential in multiple sclerosis.