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通过人TCR基因的逆转录表达,在表达人HLA-DR4的NOD/Shi-scid/γc(null)(NOG)人源化小鼠中可视化人CD4⁺ T细胞反应。

Visualization of the human CD4⁺ T-cell response in humanized HLA-DR4-expressing NOD/Shi-scid/γc(null) (NOG) mice by retrogenic expression of the human TCR gene.

作者信息

Takahashi Takeshi, Katano Ikumi, Ito Ryoji, Ito Mamoru

机构信息

Central Institute for Experimental Animals, 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.

Central Institute for Experimental Animals, 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.

出版信息

Biochem Biophys Res Commun. 2015 Jan 2;456(1):219-24. doi: 10.1016/j.bbrc.2014.11.062. Epub 2014 Nov 22.

Abstract

The development of severe immunodeficient mouse strains containing various human genes, including cytokines or HLA, has enabled the reconstitution of functional human immune systems after transplantation of human hematopoietic stem cells (HSC). Accumulating evidence has suggested that HLA-restricted antigen-specific human T-cell responses can be generated in these humanized mice. To directly monitor immune responses of human CD4(+) T cells, we introduced β-lactoglobulin (BLG)-specific T cell receptor (TCR) genes derived from CD4(+) T-cell clones of cow-milk allergy patients into HSCs, and subsequently transplanted them into NOG-HLA-DR4 transgenic/I-Aβ deficient mice (NOG-DR4/I-A(o)). In the thymus, thymocytes with BLG-specific TCR preferentially differentiated into CD4(+)CD8(-) single-positive cells. Adoptive transfer of mature CD4(+) T cells expressing the TCR into recipient NOG-DR4/I-A(o) mice demonstrated that human CD4(+) T cells proliferated in response to antigenic stimulation and produced IFN-γ in vivo, suggesting that functional T-cell reactions (especially Th1-skewed responses) were induced in humanized mice.

摘要

含有包括细胞因子或人类白细胞抗原(HLA)在内的各种人类基因的严重免疫缺陷小鼠品系的培育,使得在移植人类造血干细胞(HSC)后能够重建功能性人类免疫系统。越来越多的证据表明,在这些人源化小鼠中能够产生HLA限制的抗原特异性人类T细胞应答。为了直接监测人类CD4(+) T细胞的免疫应答,我们将源自牛奶过敏患者CD4(+) T细胞克隆的β-乳球蛋白(BLG)特异性T细胞受体(TCR)基因导入造血干细胞,随后将其移植到NOG-HLA-DR4转基因/I-Aβ缺陷小鼠(NOG-DR4/I-A(o))体内。在胸腺中,具有BLG特异性TCR的胸腺细胞优先分化为CD4(+)CD8(-)单阳性细胞。将表达该TCR的成熟CD4(+) T细胞过继转移到受体NOG-DR4/I-A(o)小鼠中,结果表明人类CD4(+) T细胞在抗原刺激下发生增殖,并在体内产生γ干扰素,这表明在人源化小鼠中诱导了功能性T细胞反应(尤其是Th1偏向性应答)。

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