Cell extrinsic alterations in splenic B cell maturation in Flt3-ligand knockout mice.
Cell extrinsic alterations in splenic B cell maturation in Flt3-ligand knockout mice.
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DOI：
10.1002/iid3.54
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发表时间：
2015-06
影响因子：
3.2
通讯作者：
Medina, Kay L
中科院分区：
文献类型：
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作者：
Dolence, Joseph J;Gwin, Kimberly A;Shapiro, Mariya B;Hsu, Fan-Chi;Shapiro, Virginia S;Medina, Kay L
骨髓中的B淋巴细胞生成对于维持多样化的外周B细胞库以抵抗感染和建立终身免疫至关重要。在Flt3配体（FL - / -）小鼠中，未成熟B细胞的产生减少，导致脾脏B细胞缺陷。在此，我们试图了解FL - / -小鼠脾脏B细胞缺陷的细胞基础。在FL - / -小鼠中发现过渡型（TS）和滤泡型（FO）B细胞显著减少，边缘区（MZ）B细胞的频率增加，但绝对数量未增加。脾脏B细胞上的BAFF - R表达以及B细胞活化因子（BAFF）的血清水平与野生型（WT）小鼠相当。混合骨髓嵌合体显示TS和FO B细胞的减少是细胞外源性的。向FL - / -小鼠施用FL可恢复TS B细胞的缺陷并使MZ区室正常化。Ki67分析显示FL - / -小鼠中TS B细胞的增殖能力显著下降。Bcl2转基因未能挽救FL - / -小鼠中的TS细胞，这表明FL缺乏与Bcl2依赖性存活途径无关。CD1d表达的上调以及过继转移实验表明FL - / -小鼠存在MZ偏移。这些发现支持Flt3信号在外周B细胞成熟中具有不可或缺的作用。
B lymphopoiesis in bone marrow (BM) is critical for maintaining a diverse peripheral B cell pool to fight infection and establish lifelong immunity. The generation of immature B cells is reduced in Flt3-ligand (FL-/-) mice leading to deficiencies in splenic B cells. Here, we sought to understand the cellular basis of the spleen B cell deficiency in FL-/- mice. Significant reductions in transitional (TS) and follicular (FO) B cells were found in FL-/- mice, and increased frequencies, but not absolute numbers, of marginal zone (MZ) B cells. BAFF-R expression on splenic B cells and serum levels of B cell activating factor (BAFF) was comparable to wildtype (WT) mice. Mixed BM chimeras revealed that the reductions in TS and FO B cells were cell extrinsic. FL administration into FL-/- mice restored the deficiency in TS B cells and normalized the MZ compartment. Ki67 analysis revealed a significant decrease in the proliferative capacity of TS B cells in FL-/- mice. A Bcl2 transgene did not rescue TS cells in FL-/- mice, uncoupling FL-deficiency to Bcl2-dependent survival pathways. Upregulation of CD1d expression and adoptive transfer experiments suggested MZ skewing in FL-/- mice. These findings support an integral role for Flt3 signaling in peripheral B cell maturation.