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<p>Regulatory B cells (Bregs) contribute to immune homeostasis via IL-10–dependent and independent pathways. To dissect additional mediators, we investigated splenic derived GM-CSF/IL-15 fusokine (GIFT15)-induced Bregs in experimental autoimmune encephalomyelitis (EAE) using transcriptomics and functional validation. Bulk RNA-seq of splenic Bregs revealed upregulation of <i>Ccl3</i>, <i>GzmB</i>, and <i>Il27</i> subunits compared to resting B cells. Functional studies showed that CCL3-deficient Bregs failed to suppress disease, whereas GzmB-deficient Bregs retained efficacy, and IL-27 receptor signaling in recipients was dispensable. Flow cytometry demonstrated that CCL3 expression correlated with FoxP3⁺ Treg and Tr1 expansion, along with CD206⁺ macrophage polarization. In the CNS, transient, tissue-dependent increases in oligodendroglial markers O4 and GalC were detected. Collectively, these findings identify CCL3 as a non-redundant effector of Breg-mediated protection, acting primarily through peripheral T-cell and myeloid remodeling, with secondary CNS impacts. These results highlight the translational potential of CCL3-competent, spleen-derived GIFT15 Bregs for therapeutic modulation of autoimmune demyelination.</p>

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Regulatory B cell CCL3 competency promotes disease resolution and oligodendrogenesis in experimental autoimmune encephalomyelitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月31日

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  • Andrea Pennati,
  • Xingyi Tang,
  • Catigan Hedican,
  • Amar Yeware,
  • Md Mahfuzur Rahman,
  • Owen A. Zeitler,
  • Shala Yuan,
  • Jacques Galipeau

摘要

Regulatory B cells (Bregs) contribute to immune homeostasis via IL-10–dependent and independent pathways. To dissect additional mediators, we investigated splenic derived GM-CSF/IL-15 fusokine (GIFT15)-induced Bregs in experimental autoimmune encephalomyelitis (EAE) using transcriptomics and functional validation. Bulk RNA-seq of splenic Bregs revealed upregulation of Ccl3, GzmB, and Il27 subunits compared to resting B cells. Functional studies showed that CCL3-deficient Bregs failed to suppress disease, whereas GzmB-deficient Bregs retained efficacy, and IL-27 receptor signaling in recipients was dispensable. Flow cytometry demonstrated that CCL3 expression correlated with FoxP3⁺ Treg and Tr1 expansion, along with CD206⁺ macrophage polarization. In the CNS, transient, tissue-dependent increases in oligodendroglial markers O4 and GalC were detected. Collectively, these findings identify CCL3 as a non-redundant effector of Breg-mediated protection, acting primarily through peripheral T-cell and myeloid remodeling, with secondary CNS impacts. These results highlight the translational potential of CCL3-competent, spleen-derived GIFT15 Bregs for therapeutic modulation of autoimmune demyelination.