Barth Syndrome (BTHS) is a rare X-linked genetic disorder caused by mutation in the TAFAZZIN gene which encodes the cardiolipin (CL) transacylase tafazzin (Taz). Taz deficiency in BTHS patients results in reduced CL in their tissues and a neutropenia which contributes to the risk of infections. However, the impact of Taz deficiency in other cells of the immune system is poorly understood. Mesenchymal stem cells (MSCs) are well known for their immune inhibitory function. We examined whether Taz-deficiency in murine MSCs impacted their ability to modulate lipopolysaccharide (LPS)-activated wild type (WT) murine B lymphocytes. MSCs from tafazzin knockdown (TazKD) mice exhibited a 50% reduction in CL compared to wild type (WT) MSCs. However, mitochondrial oxygen consumption rate and membrane potential were unaltered. In contrast, TazKD MSCs exhibited increased glycolysis compared to WT MSCs and this was associated with elevated proliferation, phosphatidylinositol-3-kinase expression and expression of the immunosuppressive markers indoleamine-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4, interleukin-10, and cluster of differentiation 59. When co-cultured with LPS-activated WT B cells, TazKD MSCs inhibited B cell proliferation and growth rate and reduced B cell secretion of IgM to a greater extent than B cells co-cultured with WT MSCs. In addition, co-culture of LPS-activated WT B cells with TazKD MSCs induced B cell differentiation toward potent immunosuppressive phenotypes including interleukin-10 secreting plasma cells and B regulatory cells compared to activated B cells co-cultured with WT MSCs. These results indicate that Taz deficiency in MSCs enhances MSCs-mediated immunosuppression of activated B lymphocytes.

中文翻译：

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小鼠间充质干细胞中的 Tafazzin 缺乏增强其免疫抑制并损害活化的 B 淋巴细胞免疫功能

巴特综合征 (BTHS) 是一种罕见的 X 连锁遗传病，由编码心磷脂 (CL) 转酰酶 tafazzin (Taz) 的 TAFAZZIN 基因突变引起。BTHS 患者的 Taz 缺乏导致其组织中的 CL 降低和中性粒细胞减少，这会增加感染的风险。然而，Taz 缺乏对免疫系统其他细胞的影响知之甚少。间充质干细胞 (MSC) 以其免疫抑制功能而闻名。我们检查了鼠 MSC 中的 Taz 缺陷是否影响了它们调节脂多糖 (LPS) 激活的野生型 (WT) 鼠 B 淋巴细胞的能力。与野生型 (WT) MSCs 相比，来自 tafazzin 敲低 (TazKD) 小鼠的 MSCs 的 CL 减少了 50%。然而，线粒体耗氧率和膜电位没有改变。相比之下，与 WT MSCs 相比，TazKD MSCs 表现出增加的糖酵解，这与增殖、磷脂酰肌醇-3-激酶表达和免疫抑制标志物吲哚胺-2,3-双加氧酶、细胞毒性 T-淋巴细胞相关蛋白 4、白细胞介素-10、和分化簇 59. 当与 LPS 激活的 WT B 细胞共培养时，TazKD MSC 比与 WT MSC 共培养的 B 细胞更能抑制 B 细胞增殖和生长速率并减少 B 细胞 IgM 的分泌。此外，与与 WT MSC 共培养的活化 B 细胞相比，LPS 活化的 WT B 细胞与 TazKD MSC 的共培养诱导 B 细胞分化为有效的免疫抑制表型，包括分泌白细胞介素 10 的浆细胞和 B 调节细胞。