Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity
Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity
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DOI：
10.1073/pnas.1120237109
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发表时间：
2012-04-10
影响因子：
11.1
通讯作者：
Shizuru, Judith A.
中科院分区：
文献类型：
--
作者：
Mueller, Antonia M. S.;Shashidhar, Sumana;Shizuru, Judith A.
免疫功能低下是异基因造血细胞移植成功的根本障碍。成熟的移植物T细胞被认为在移植后早期提供免受感染的保护，但可能导致危及生命的移植物抗肿瘤。宿主疾病人类巨细胞病毒是移植后的主要病原体。我们研究了对小鼠同源物，小鼠巨细胞病毒（MCMV），在致死性照射小鼠异基因纯化造血干细胞（HSC）或补充T细胞或T细胞亚群的HSC的反应。出乎意料的是，与HSC加自体T细胞的受体相比，纯化HSC的受体获得了上级抗病毒应答。此外，用CD8（+）记忆或MCMV特异性T细胞补充纯化的HSC移植物导致增强的抗病毒反应性。移植后淋巴细胞减少促进MCMV特异性T细胞的大量扩增时，没有竞争的供体T细胞。在纯HSC的接受者中，幼稚和记忆T细胞和先天淋巴样细胞群发育。相反，大量T细胞受体中的淋巴池由效应记忆细胞主导。这些研究表明，与非成熟T细胞相比，纯HSC移植允许针对病毒病原体的上级保护性免疫。这种简化移植模型揭示了移植物组成对宿主、新产生的和成熟的转移T细胞再生的影响，并强调了大量供体T细胞的有害作用。我们的研究结果使我们得出结论，由纯化的HSC组成的移植物为选定的抗原特异性细胞的体内扩增提供了最佳平台，同时允许初始T细胞库的重建。
Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8(+) memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.