Human T cells depend on functional calcineurin, tumour necrosis factor-α and CD80/CD86 for expansion and activation in mice
Human T cells depend on functional calcineurin, tumour necrosis factor-α and CD80/CD86 for expansion and activation in mice
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DOI：
10.1111/cei.12051
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发表时间：
2013-05-01
影响因子：
4.6
通讯作者：
Haase, C.
中科院分区：
文献类型：
--
作者：
Sondergaard, H.;Kvist, P. H.;Haase, C.
调节失调的T细胞是几种自身免疫和炎症性疾病的标志；因此，在体内研究人类T细胞的模型是有利的，但受到缺乏对小鼠人类T细胞功能的了解的限制。以非肥胖型糖尿病(NOD)、重症联合免疫缺陷(SCID)或重组激活基因-1(RAG1)/及人外周血单个核细胞(PBMC)重组的白细胞介素2受体-γ链(IL-2R)/小鼠为研究对象，研究了人T细胞在小鼠体内扩增和活化的机制。将人PBMCs注射到小鼠体内，通过多克隆扩增和激活人的功能性T细胞和产生人的细胞因子，导致一致的异种移植。人类T细胞的增殖与移植物抗宿主病(GVHD)样疾病的发展相吻合，观察到的症状包括体重减轻、多器官免疫渗透和肝脏损伤。CD8+T细胞本身就足以扩增，是疾病发展所必需的；相比之下，仅有CD4+T细胞扩增，但不会引发急性疾病，而是通过CD25+CD4+T细胞发挥调节能力。使用不同的抗炎化合物，我们证明了几种T细胞激活途径控制T细胞的增殖和疾病的发展，包括通过CD80/CD86途径的钙调神经磷酸酶、肿瘤坏死因子和共刺激信号，表明人类T细胞在小鼠的扩增和激活过程中使用的不同的作用模式以及该模型的药理学相关性。总体而言，这些数据提供了对人类T细胞在小鼠体内扩增和激活过程中使用的机制的洞察，我们推测，注射PBMC的小鼠可能有助于在体内研究人类T细胞的内在功能，并测试T细胞靶向化合物。
Dysregulated T cells are a hallmark of several autoimmune and inflammatory diseases; thus, models to study human T cells in vivo are advantageous, but limited by lacking insight into human T cell functionality in mice. Using non-obese diabetic (NOD), severe combined immunodeficient (SCID) or recombination activating gene-1 (RAG1)/ and interleukin-2 receptor gamma-chain (IL-2R)/ mice reconstituted with human peripheral blood mononuclear cells (PBMCs), we have studied the mechanisms of human T cell expansion and activation in mice. Injection of human PBMCs into mice caused consistent xeno-engraftment with polyclonal expansion and activation of functional human T cells and production of human cytokines. Human T cell expansion coincided with development of a graft-versus-host disease (GVHD)-like condition observed as weight loss, multi-organ immune infiltration and liver damage. CD8+ T cells alone were sufficient for expansion and required for disease development; in contrast, CD4+ T cells alone expanded but did not induce acute disease and, rather, exerted regulatory capacity through CD25+CD4+ T cells. Using various anti-inflammatory compounds, we demonstrated that several T cell-activation pathways controlled T cell expansion and disease development, including calcineurin-, tumour necrosis factor- and co-stimulatory signalling via the CD80/CD86 pathway, indicating the diverse modes of action used by human T cells during expansion and activation in mice as well as the pharmacological relevance of this model. Overall, these data provide insight into the mechanisms used by human T cells during expansion and activation in mice, and we speculate that PBMC-injected mice may be useful to study intrinsic human T cell functions in vivo and to test T cell-targeting compounds.