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bioRxiv · 10.64898/2026.09.01.748682

Pathogenic T-bet+ memory B cells worsen multiple sclerosis through myeloid cell activation

Jain, R. W.·Goiko, M.·Mendes, A.·Xue, S.·Zein, S.·Gorter, R. P.·Morch, M. T.·Prat, A.·Li, R.·Yong, V. W.
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Abstract

Depletion of B cells in multiple sclerosis (MS) is beneficial yet there is no defined pathogenic B cell subset in MS. Here, we demonstrate that T-bet+ memory B cells are rare in control human brain specimens but are found in MS lesions. Transfer of murine T-bet+ memory B cells into mice with ongoing experimental autoimmune encephalomyelitis (EAE), a model of MS, worsened their disability and demyelination. Microglia/macrophage density increased in central nervous system parenchyma even though B cells mostly remained in barriers. In culture, secreted factors from T-bet+ memory B cells promoted macrophage migration. IFN-{gamma} produced by T-bet+ memory B cells activated microglia to secrete chemokines that further enabled macrophage migration. Consistent with their age-associated elevation, conditional deletion of T-bet in B cells lowered EAE severity in aged but not young mice. We define T-bet+ memory B cells as pathogenic in EAE and MS through their IFN-{gamma}-facilitated interactions with microglia/macrophages.

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Jain, R. W., Goiko, M., Mendes, A., Xue, S., Zein, S., Gorter, R. P., Morch, M. T., Prat, A., Li, R., Yong, V. W.. 2026-09-05. Pathogenic T-bet+ memory B cells worsen multiple sclerosis through myeloid cell activation. https://doi.org/10.64898/2026.09.01.748682

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