Early T lineage progenitors

描述（由申请人提供）：胸腺中的T细胞由骨髓（BM）中的造血干细胞（HSC）发育而来，但通过血液将BM中的HSC连接到胸腺中的早期T谱系祖细胞的细胞中间体仍不清楚。这项工作的长期目标是阐明早期T细胞发育的细胞和分子基础。最近已经确定，胸腺中的早期T谱系祖细胞（ETP）来源于不同于先前描述的普通淋巴样祖细胞（CLP）的BM祖细胞群体，并且导致T和B细胞的途径比先前认识到的更早地分叉。提出实验以进一步定义和表征中间群体，所述中间群体从BM中的多能祖细胞通过血液中的循环祖细胞，最终导致胸腺内的ETP及其下游T谱系后代。 虽然已知细胞因子和Notch信号对早期T细胞发育至关重要，但接收和整合这些多种信号的细胞中间体在很大程度上未被表征。Notch信号可能在胸腺定殖后不久被血液传播的造血祖细胞接收，但是这些信号在其中操作以导致T谱系定型的ETP子集也没有被表征。我们的目标是鉴定从骨髓中的HSC到胸腺中的T谱系细胞的完整细胞谱系。了解T细胞系发育中的关键细胞中间体对于了解这一过程中的疾病是必要的，并且在各种诊断和治疗努力中具有基本和关键的用途。因此，理解衰老中的T细胞缺陷、T谱系细胞中的恶性转化过程以及纠正T细胞发育和功能缺陷的基因治疗都需要理解将HSC连接到T细胞的造血步骤。

DESCRIPTION (provided by applicant): T cells in thymus develop from hematopoietic stem cells (HSCs) in bone marrow (BM), but the cellular intermediates linking HSCs in BM via blood to early T lineage progenitors in thymus remain poorly defined. The long-term goal of the proposed work is to elucidate the cellular and molecular basis for early T cell development. It has recently been determined that early T lineage progenitors (ETPs) in thymus derive from a BM progenitor population distinct from previously described common lymphoid progenitors (CLPs), and that the pathways leading to T and B cells diverge earlier than had been previously appreciated. Experiments are proposed to further define and characterize the intermediate populations that lead from multipotent progenitors in BM, through a circulating progenitor cell in blood, eventually leading to ETPs and their downstream T lineage progeny within the thymus. While cytokines and Notch signals are known to be critical for early T cell development, the cellular intermediates receiving and integrating these multiple signals are largely uncharacterized. Notch signals are probably received by blood-borne hematopoietic progenitors shortly after thymic colonization, but ETP subsets within which these signals operate to result in T lineage commitment are also not characterized. Our goal is to identify a complete lineage of cells leading from HSCs in bone marrow to T lineage cells in thymus. An understanding of the key cellular intermediates in T lineage development is necessary to understand disorders in this process, and will be of basic and critical use in a wide variety of diagnostic and therapeutic endeavors. Hence understanding the T cell defects in aging, the process of malignant transformation in T lineage cells, and gene therapy to correct defects of T cell development and function all require that the steps of hematopoiesis linking HSCs to T cells be understood.