Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2rγnull humanized mice
Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2rγnull humanized mice
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DOI：
10.1073/pnas.1000475107
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发表时间：
2010-07-20
影响因子：
11.1
通讯作者：
Ishikawa, Fumihiko
中科院分区：
文献类型：
--
作者：
Shultz, Leonard D.;Saito, Yoriko;Ishikawa, Fumihiko
尽管人源化小鼠模型对人类免疫学研究做出了重大贡献，但在小鼠胸腺环境中发育的人类T细胞未能表现出HLA限制性功能。为了实现HLA限制性人类免疫应答，我们创建了具有HLA I类重链和轻链的纯合表达的免疫受损的非肥胖糖尿病/SCID/IL 2 rg（null）菌株（NSG）（NSG-HLA-A2/HHD）。将纯化的Lin-CD 34 + CD 38-人造血干细胞移植到NSG-HLA-A2/HHD新生儿中导致受体骨髓和脾脏中人CD 4+和CD 8 + TCR α β + T细胞以及CD 4-CD 8-和CD 8 + TCR γ δ +细胞的发育。人类细胞毒性T淋巴细胞（CTL）在功能上变得成熟，这一点可以通过产生对应于从原始CTL到效应记忆CTL的表型转变的颗粒酶来证明。在这些受体中，人Th 17细胞与Th 1和Th 2细胞一起沿着发育。人源化NSG-HLA-A2/HHD受体中的EB病毒（EBV）感染导致主要由人B细胞和分散的人T细胞组成的淋巴组织增生性病变的形成。在受体中发育的人CTL以HLA限制性方式识别EBV衍生肽，并对EBV感染的人B细胞产生HLA限制性细胞毒性。具有功能性HLA限制性T细胞和罕见T细胞亚群的一致代表性的HLA表达人源化小鼠克服了人类免疫学中的主要限制，并且用作用于研究针对病原体的人类免疫应答和用于开发针对人类疾病的治疗策略的有用模型。
Whereas humanized mouse models have contributed significantly to human immunology research, human T cells developing in mouse thymic environment fail to demonstrate HLA-restricted function. To achieve HLA-restricted human immune response, we created an immune-compromised non-obese diabetic/SCID/IL2rg(null) strain (NSG) with homozygous expression of HLA class I heavy chain and light chain (NSG-HLA-A2/HHD). Transplantation of purified Lin-CD34+ CD38- human hematopoietic stem cells into NSG-HLA-A2/HHD newborns resulted in the development of human CD4+ and CD8+ TCR alpha beta+ T cells and CD4-CD8- and CD8+ TCR gamma delta+ cells in recipient bone marrow and spleen. Human cytotoxic T lymphocytes (CTLs) become functionally mature, as evidenced by the production of granzyme corresponding to phenotypic transition from nave to effector memory CTLs. In these recipients, human Th17 cells developed along with Th1 and Th2 cells. Epstein-Barr virus (EBV) infection in the humanized NSG-HLA-A2/HHD recipients resulted in the formation of lymphoproliferative lesions consisting mainly of human B cells with scattered human T cells. Human CTLs developing in the recipients recognized EBV-derived peptides in an HLA-restricted manner and exerted HLA-restricted cytotoxicity against EBV-infected human B cells. The HLA-expressing humanized mouse with functional HLA-restricted T cells and consistent representation of rare T-cell subsets overcomes a major constraint in human immunology, and serves as a useful model for investigation of human immune responses against pathogens and for the development of therapeutic strategies against human diseases.