Early Events in Mammalian B-Cell Differentiation

描述（由申请人提供）：项目摘要/摘要随着功能特化细胞类型的发现，我们对免疫系统的理解正在取得非凡的进展。然而，新的数据开始揭示，造血干细胞（HSC）发育的过程比通常认为的更复杂，控制也不那么严格。长期以来，教科书一直描述HSC和B淋巴细胞之间的简单关系，但现在看来，祖细胞失去成为B细胞的选择并被导向其他命运的分支点并不只有一个。相反，对B血统的奉献和坚定承诺是一个渐进的过程，可以根据环境线索发生巨大变化。关于内源性信号，如细胞因子、激素和细胞粘附分子提供的信号，还有很多东西需要了解。此外，我们有新的观察结果表明，维甲酸可以加速淋巴细胞的形成过程，其对骨髓的影响值得进一步研究。例如，这些广泛使用的处方药有望成为促进免疫系统恢复的药物。我们正在将特殊的基因敲入小鼠与细胞分选、细胞培养和移植技术相结合，以系统地研究这些问题和其他问题。 我们的实验室发现，Toll样受体（TLR）在造血细胞上表达，使这些细胞能够识别细菌/病毒产物，并且已经确定了这种相互作用的几个重要结果。例如，TLR配体刺激干细胞进入周期并开始分化，而骨髓限制性细胞完成其成熟。配体阻止B细胞的产生并导致淋巴细胞祖细胞产生几种类型的树突细胞。虽然这些新机制可能具有生存价值，但我们认为也存在干细胞和祖细胞需要保护免受此类物质影响的情况。我们的实验室正在使用确定的培养条件来研究与淋巴祖细胞的明显重编程相关的机制。此外，我们正在追踪HSV感染小鼠中的相同现象。 项目叙述：我们的骨髓必须不断制造新的血细胞，包括负责抗体形成和抵御感染的细胞。患者在化疗或移植后容易感染，但我们的数据表明，它可能会加速免疫系统的恢复。对免疫系统发育早期阶段的基本了解可能会为改善受损组织的愈合以及更好地治疗癌症和自身免疫性疾病指明方向。

DESCRIPTION (provided by applicant): Project Summary/Abstract Extraordinary advances are being made in our understanding of the immune system, with discovery of functionally specialized cell types. However, new data are beginning to reveal that the process by which hematopoietic stem cells (HSC) develop is more complex and less rigidly controlled than generally believed. Textbooks have long depicted simple relationships between HSC and B lymphocytes, but it now appears that there is not just one branch point where progenitors lose the option of becoming B cells and are directed to other fates. Rather, dedication and firm commitment to the B lineage is a gradual process and can be dramatically altered in response to environmental cues. There is still much to learn about endogenous cues such as those provided by cytokines, hormones and cell adhesion molecules. In addition, we have new observations suggesting that retinoids can accelerate the process of lymphocyte formation and their effects on the bone marrow merit further study. For example, these widely prescribed drugs hold promise as agents for boosting recovery of the immune system. We are combining special knock-in mice with cell sorting, cell culture and transplantation techniques to systematically investigate these and other questions. Our lab discovered that Toll-like receptors (TLR) are expressed on hematopoietic cells, allowing these cells to recognize bacterial/viral products and several important outcomes of this interaction have already been identified. For example, TLR ligands stimulate stem cells to enter cycle and begin differentiating, while myeloid restricted cells complete their maturation. The ligands arrest B cell production and cause lymphocyte progenitors to generate several types of dendritic cells. While these new mechanisms may have survival value, we believe there are also circumstances where stem and progenitor cells need to be protected from such substances. Our lab is using defined culture conditions to study mechanisms associated with an apparent re-programming of lymphoid progenitors. In addition, we are tracking the same phenomena in HSV infected mice. Project Narrative: Our bone marrow must constantly make new blood cells, including cells responsible for antibody formation and defense against infections. Patients are vulnerable to infections following chemotherapy or transplantation, but our data suggest that it may be possible to accelerate recovery of the immune system. Basic understanding of early stages of immune system development may point the way to improved healing of damaged tissues as well as better treatments for cancer and autoimmune diseases.