Riether C, Schürch C M, Ochsenbein A F
Tumor Immunology, Department of Clinical Research, University of Bern, Bern, Switzerland.
1] Tumor Immunology, Department of Clinical Research, University of Bern, Bern, Switzerland [2] Institute of Pathology, University of Bern, Bern, Switzerland.
Cell Death Differ. 2015 Feb;22(2):187-98. doi: 10.1038/cdd.2014.89. Epub 2014 Jul 4.
Hematopoietic stem cells (HSCs) are rare, multipotent cells that generate via progenitor and precursor cells of all blood lineages. Similar to normal hematopoiesis, leukemia is also hierarchically organized and a subpopulation of leukemic cells, the leukemic stem cells (LSCs), is responsible for disease initiation and maintenance and gives rise to more differentiated malignant cells. Although genetically abnormal, LSCs share many characteristics with normal HSCs, including quiescence, multipotency and self-renewal. Normal HSCs reside in a specialized microenvironment in the bone marrow (BM), the so-called HSC niche that crucially regulates HSC survival and function. Many cell types including osteoblastic, perivascular, endothelial and mesenchymal cells contribute to the HSC niche. In addition, the BM functions as primary and secondary lymphoid organ and hosts various mature immune cell types, including T and B cells, dendritic cells and macrophages that contribute to the HSC niche. Signals derived from the HSC niche are necessary to regulate demand-adapted responses of HSCs and progenitor cells after BM stress or during infection. LSCs occupy similar niches and depend on signals from the BM microenvironment. However, in addition to the cell types that constitute the HSC niche during homeostasis, in leukemia the BM is infiltrated by activated leukemia-specific immune cells. Leukemic cells express different antigens that are able to activate CD4(+) and CD8(+) T cells. It is well documented that activated T cells can contribute to the control of leukemic cells and it was hoped that these cells may be able to target and eliminate the therapy-resistant LSCs. However, the actual interaction of leukemia-specific T cells with LSCs remains ill-defined. Paradoxically, many immune mechanisms that evolved to activate emergency hematopoiesis during infection may actually contribute to the expansion and differentiation of LSCs, promoting leukemia progression. In this review, we summarize mechanisms by which the immune system regulates HSCs and LSCs.
造血干细胞（HSCs）是一种罕见的多能细胞，可通过所有血细胞谱系的祖细胞和前体细胞产生。与正常造血过程类似，白血病也是分层组织的，白血病细胞亚群，即白血病干细胞（LSCs），负责疾病的起始和维持，并产生更多分化的恶性细胞。尽管LSCs存在基因异常，但它们与正常HSCs具有许多共同特征，包括静止、多能性和自我更新能力。正常HSCs存在于骨髓（BM）的特殊微环境中，即所谓的HSC龛，它对HSC的存活和功能起着关键的调节作用。包括成骨细胞、血管周围细胞、内皮细胞和间充质细胞在内的多种细胞类型都对HSC龛有贡献。此外，BM还作为初级和次级淋巴器官，容纳各种成熟的免疫细胞类型，包括T细胞和B细胞、树突状细胞和巨噬细胞，它们也对HSC龛有贡献。来自HSC龛的信号对于调节BM应激后或感染期间HSCs和祖细胞的需求适应性反应是必要的。LSCs占据相似的龛位，并依赖于BM微环境的信号。然而，除了在稳态期间构成HSC龛的细胞类型外，在白血病中，BM还被活化的白血病特异性免疫细胞浸润。白血病细胞表达不同的抗原，能够激活CD4(+)和CD8(+) T细胞。有充分的文献记载，活化的T细胞有助于控制白血病细胞，人们希望这些细胞能够靶向并消除对治疗耐药的LSCs。然而，白血病特异性T细胞与LSCs之间的实际相互作用仍不明确。矛盾的是，许多在感染期间进化以激活应急造血的免疫机制实际上可能有助于LSCs的扩增和分化，促进白血病进展。在这篇综述中，我们总结了免疫系统调节HSCs和LSCs的机制。
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