Commitment and efficiency of extrathymic T cell precursors - towards improved T lineage reconstitution after bone marrow transplantation

T细胞在胸腺中发育，但最终来源于骨髓（BM）中的造血干细胞（HSC）。理解HSC与胸腺内T谱系定向祖细胞之间的发育步骤对于理解T谱系细胞中的癌症、对于改善BM移植后的T细胞重建、对于治愈缺陷性T细胞发育或功能的基因治疗方法是重要的，并且还将与改善衰老中的免疫缺陷相关。已经描述了几种胸腺外候选祖细胞，其范围从多能细胞到淋巴样细胞定向祖细胞，甚至主要是T谱系定向前体。然而，不同祖细胞在生理条件下产生T细胞的效率和决定T谱系定型的信号在很大程度上仍然是难以捉摸的。在这里，我们建议在体内和体外研究不同的T细胞系前体的分化途径，无论是表型和分子。分子分析将集中在诱导T谱系定型的信号上，例如通过Notch途径传递的信号。第二个主要目标是比较不同胸腺外T细胞前体的胸腺归巢和T细胞生成的功效。最后，我们将把我们的发现转化为人类系统。这些实验将有助于澄清在生理和病理生理条件下不同的胸腺外前体对T细胞发育的相对贡献，从而最终可能导致改善BM移植方案。

T cells develop in the thymus, but ultimately derive from Hematopoietic Stem Cells (HSC) in the bone marrow (BM). An understanding of developmental steps linking HSC to intrathymic T lineage-committed progenitors is important for understanding cancer in T lineage cells, for improving T cell reconstitution after BM transplantation, for gene therapy approaches to curing defective T cell development or function, and will also be relevant for ameliorating immunological defects in aging. Several extrathymic candidate progenitors have been described that range from pluripotent cells, to lymphoid cell committed progenitors and even largely T lineage committed precursors. However, the efficiency of the different progenitors to generate T cells under physiological conditions and signals that determine commitment to the T lineage remain largely elusive. Here we propose to study the differentiation pathways of different T lineage precursors in vivo and in vitro, both phenotypically and molecularly. The molecular analysis will focus on the signals inducing commitment to the T lineage, such as signals transmitted via the Notch pathway. In a second major aim the efficacy of thymus homing and T cell generation of different extrathymic T cell precursors will be compared. Finally, we will translate our findings to the human system. These experiments will help clarify the relative contribution of different extrathymic precursors to T cell development both under physiological and pathophysiological conditions and may thus ultimately lead to improved BM transplantation protocols.