Johnson Kristen, Shapiro-Shelef Miriam, Tunyaplin Chainarong, Calame Kathryn
Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Mol Immunol. 2005 May;42(7):749-61. doi: 10.1016/j.molimm.2004.06.039. Epub 2005 Jan 20.
We are studying transcriptional control of critical developmental decision points in B lymphocytes. Commitment to the B-lymphocyte lineage is dependent on the transcriptional regulator Pax5 and committed B lymphocytes represent the first developmental stage when V(H)-to-DJ recombination occurs in the immunoglobulin (Ig) heavy chain locus. We summarize our recent studies showing that methylation of histone H3 lysine 9, a heterochromatic chromatin modification, is present in the Ig V(H) region in hematopoietic progenitors and in non-B lineage hematopoietic cells. Pax5 is both necessary and sufficient to remove this heterochromatic mark in B cells. Using genetically altered mice, we have shown that terminal differentiation of B cells to memory and Ig-secreting plasma cells depends on the transcriptional repressor Blimp-1. Recent studies demonstrating a requirement for Blimp-1 in the formation of pre-plasma memory B cells, Ig-secreting plasma cells as well as preliminary data suggesting a requirement for Blimp-1 in the maintenance of long-lived plasma cells are summarized. We also summarize our recent studies on the regulation of Blimp-1, showing direct repression by Bcl-6 and providing evidence for activation by NF-kappaB following toll-like receptor signaling.
我们正在研究B淋巴细胞关键发育决策点的转录调控。向B淋巴细胞谱系的定向分化依赖于转录调节因子Pax5，而定向的B淋巴细胞代表免疫球蛋白（Ig）重链基因座中发生V(H) - DJ重组的第一个发育阶段。我们总结了我们最近的研究，这些研究表明组蛋白H3赖氨酸9的甲基化，一种异染色质染色质修饰，存在于造血祖细胞和非B谱系造血细胞的Ig V(H)区域。Pax5对于在B细胞中去除这种异染色质标记既必要又充分。利用基因改造小鼠，我们已经表明B细胞向记忆细胞和分泌Ig的浆细胞的终末分化依赖于转录抑制因子Blimp-1。总结了最近的研究，这些研究证明了Blimp-1在预浆记忆B细胞、分泌Ig的浆细胞形成中的必要性，以及初步数据表明Blimp-1在长寿浆细胞维持中的必要性。我们还总结了我们最近对Blimp-1调控的研究，显示了Bcl-6的直接抑制作用，并提供了Toll样受体信号传导后NF-κB激活的证据。
