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首页> 美国卫生研究院文献>Clinical and Experimental Immunology >Human T cells depend on functional calcineurin tumour necrosis factor-α and CD80/CD86 for expansion and activation in mice
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Human T cells depend on functional calcineurin tumour necrosis factor-α and CD80/CD86 for expansion and activation in mice

机译：人T细胞依赖功能性钙调神经磷酸酶肿瘤坏死因子-α和CD80 / CD86来在小鼠中扩增和激活

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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-2Rγ)−/− 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-α 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.
机译：T细胞失调是几种自身免疫和炎性疾病的标志。因此，在体内研究人类T细胞的模型是有利的，但是由于缺乏对小鼠中人​​类T细胞功能的了解而受到限制。使用非肥胖型糖尿病（NOD），严重的联合免疫缺陷（SCID）或重组激活基因1（RAG1）-/-和白介素2受体γ链（IL-2Rγ）用人类外周血单核细胞（PBMC）重构的-/-小鼠，我们研究了人类T细胞在小鼠中扩增和激活的机制。将人PBMC注射入小鼠引起一致的异种移植，具有多克隆扩增和功能性人T细胞活化以及人细胞因子的产生。人的T细胞扩增与体重减轻，多器官免疫浸润和肝损害相一致，发生了移植物抗宿主病（GVHD）样疾病。单独的CD8 + T细胞足以扩增，并且是疾病发展所必需的。相反，单独的CD4 + T细胞会扩增，但不会诱发急性疾病，而是通过CD25 + CD4 + T细胞发挥调节作用。使用各种抗炎化合物，我们证明了几种T细胞活化途径可控制T细胞扩增和疾病发展，包括钙调神经磷酸酶，肿瘤坏死因子-α和通过CD80 / CD86途径的共刺激信号传导，表明了多种模式人类T细胞在小鼠的扩张和激活过程中使用的作用以及该模型的药理学意义。总体而言，这些数据深入了解了人类T细胞在小鼠的扩增和激活过程中所使用的机制，并且我们推测，注射PBMC的小鼠可用于研究体内人类T细胞的固有功能并测试靶向T细胞的化合物。

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