Aberrant gene expression by CD25+CD4+ immunoregulatory T cells in autoimmune-prone rats carrying the human T cell leukemia virus type-I gene
Aberrant gene expression by CD25+CD4+ immunoregulatory T cells in autoimmune-prone rats carrying the human T cell leukemia virus type-I gene
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DOI：
10.1093/intimm/dxh238
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发表时间：
2005-06-01
影响因子：
4.4
通讯作者：
Yoshiki, T
中科院分区：
文献类型：
--
作者：
Hayase, H;Ishizu, A;Yoshiki, T
在病毒长末端重复序列启动子控制下表达人T细胞白血病病毒I型env-pX基因的转基因大鼠（env-pX大鼠）发生系统性自身免疫性疾病。在疾病表现之前，这些大鼠中的CD 25（+）CD 4（+）T（T-reg）细胞的免疫抑制功能受损。由于env-pX大鼠的T细胞分化出现紊乱，我们假设T-reg细胞的损伤可能是由胸腺中的分化失败引起的。然而，env-pX和野生型大鼠之间的相互骨髓转移表明，与胸腺框架无关的转基因的直接影响诱导了T-reg细胞的异常。为了鉴定分子变化，在env-pX和野生型T-reg细胞之间进行比较分析。Foxp 3基因和细胞表面标志物的表达支持env-pX T-reg细胞的幼稚表型。基因表达的阵列分析显示了一些有趣的概况，例如，在env-pX T-reg细胞中与Janus激酶/信号转导子和转录激活子（JAK/STAT）途径相关的基因的上调。此外，抑制JAK/STAT信号的细胞因子信号传导抑制因子（SOCS）家族基因的表达在env-pX T-reg细胞中极低。这些发现表明，转基因可能介导的SOCS家族基因的下调，随后通过JAK/STAT途径的过量信号可能导致env-pX T-reg细胞的功能丧失。我们认为，在我们的自身免疫易感大鼠模型中的T-reg细胞的病理学的调查可能有助于了解T-reg细胞在人类自身免疫性疾病中的作用。
Transgenic rats expressing the env-pX gene of human T cell leukemia virus type-I under the control of the viral long terminal repeat promoter (env-pX rats) developed systemic autoimmune diseases. Prior to disease manifestation, the immunosuppressive function of CD25(+)CD4(+) T (T-reg) cells was impaired in these rats. Since T cell differentiation appeared to be disordered in env-pX rats, we assumed that the impairment of T-reg cells might be caused by an abortive differentiation in the thymus. However, reciprocal bone marrow transfers between env-pX and wild-type rats revealed that direct effects of the transgene unrelated to the thymus framework induced the abnormality of T-reg cells. To identify molecular changes, comparative analyses were done between env-pX and wild-type T-reg cells. Expression of the Foxp3 gene and cell-surface markers supported a naive phenotype for env-pX T-reg cells. Array analyses of gene expression showed some interesting profiles, e.g. up-regulation of genes associated with the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways in env-pX T-reg cells. Additionally, expression of the suppressor of cytokine signaling (SOCS) family genes, which inhibit the JAK/STAT signals, was extremely low in env-pX T-reg cells. These findings suggest that the transgene may mediate the down-regulation of the SOCS family genes and that subsequent excess signals through the JAK/STAT pathways may result in the loss of function of env-pX T-reg cells. We suggest that investigation of the pathology of T-reg cells in our autoimmune-prone rat model may aid in understanding the roles of T-reg cells in human autoimmune diseases.