RAG-1 and Ly6D Independently Reflect Progression in the B Lymphoid Lineage

Common lymphoid progenitors (CLPs) are thought to represent major intermediates in the transition of hematopoietic stem cells (HSCs) to B lineage lymphocytes. However, it has been obvious for some time that CLPs are heterogeneous, and there has been controversy concerning their differentiation potential. We have now resolved four Flt3+ CLP subsets that are relatively homogenous and capable of forming B cells. Differentiation potential and gene expression patterns suggest Flt3+ CLPs lacking both Ly6D and RAG-1 are the least differentiated. In addition to B cells, they generate natural killer (NK) and dendritic cells (DCs). At the other extreme is a subset of the recently described Flt3+ Ly6D+ CLPs that have a history of RAG-1 expression and are B lineage restricted. These relatively abundant and potent CLPs were depleted within 48 hours of acute in vivo estrogen elevation, suggesting they descend from hormone regulated progenitors. This contrasts with the hormone insensitivity of other CLP subsets that include NK lineage progenitors. This progenitor heterogeneity and differentiation complexity may add flexibility in response to environmental changes. Expression of RAG-1 and display of Ly6D are both milestone events, but they are neither synchronized nor dependent on each other.

一般认为，共同淋巴祖细胞（Common lymphoid progenitors, CLPs）是造血干细胞（hematopoietic stem cells, HSCs）向B系淋巴细胞分化过程中的主要中间过渡群体。但长期以来学界已清晰认识到CLPs具有异质性，其分化潜能始终存在学术争议。本研究现已鉴定出4种相对均一且具备B细胞分化能力的Flt3+ CLP亚群。分化潜能与基因表达谱分析结果显示，同时缺失Ly6D与重组激活基因1（Recombination Activating Gene 1, RAG-1）的Flt3+ CLPs分化程度最低。除B细胞外，这类祖细胞还可分化为自然杀伤（natural killer, NK）细胞与树突状细胞（dendritic cells, DCs）。与之相对的是近期被报道的一类Flt3+ Ly6D+ CLP亚群，该亚群曾表达RAG-1且仅具备B系分化限制性。这类CLP数量相对丰富且分化潜能较强，在体内急性雌激素水平升高后的48小时内即被耗竭，提示其起源于激素调控的祖细胞群体。这与其他包含NK系祖细胞的CLP亚群的激素不敏感性形成鲜明对比。这种祖细胞的异质性与分化复杂性或可为免疫系统响应环境变化提供灵活性。RAG-1的表达与Ly6D的膜表面展示均为淋巴细胞分化过程中的标志性事件，但二者既不同步发生，也不存在相互依赖关系。