Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5820-5. doi: 10.1073/pnas.1120237109. Epub 2012 Mar 22.
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.
免疫功能受损是异体造血细胞移植成功的根本障碍。成熟的移植物 T 细胞被认为可以在移植后早期提供抗感染保护，但也可能导致危及生命的移植物抗宿主病。人巨细胞病毒（CMV）是移植后主要的病原体。我们研究了在接受同种异体纯化造血干细胞（HSCs）或补充有 T 细胞或 T 细胞亚群的 HSCs 的致死性照射小鼠中，针对鼠 CMV（MCMV）的反应性。出乎意料的是，与接受 HSC 加未选择的 bulk T 细胞的受体相比，接受纯化 HSC 的受体产生了更好的抗病毒反应。此外，用 CD8+记忆或 MCMV 特异性 T 细胞补充纯化 HSC 移植物可增强抗病毒反应。移植后淋巴细胞减少症促进了大量 MCMV 特异性 T 细胞的扩增，而没有竞争性的供体 T 细胞存在。在接受纯 HSC 的受体中，幼稚和记忆 T 细胞以及固有淋巴细胞群发育。相比之下，在接受 bulk T 细胞的受体中，淋巴细胞池主要由效应记忆细胞组成。这些研究表明，与未选择的成熟 T 细胞相比，纯 HSC 移植可提供针对病毒病原体的更好保护免疫。这种简化的移植模型揭示了移植物组成对宿主、新生成和成熟转移 T 细胞再生的影响，并强调了 bulk 供体 T 细胞的有害影响。我们的研究结果表明，由纯化的 HSCs 组成的移植物为体内扩增选定的抗原特异性细胞提供了最佳平台，同时允许重建幼稚 T 细胞池。
