Transcriptional control of impaired Th1 responses in patent lymphatic filariasis by T-box expressed in T cells and suppressor of cytokine signaling genes
Transcriptional control of impaired Th1 responses in patent lymphatic filariasis by T-box expressed in T cells and suppressor of cytokine signaling genes
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DOI：
10.1128/iai.73.6.3394-3401.2005
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发表时间：
2005-06-01
影响因子：
3.1
通讯作者：
Nutman, TB
中科院分区：
文献类型：
--
作者：
Babu, S;Kumaraswami, V;Nutman, TB
T-bet（T细胞中表达的T-box）和加塔-3是在Th 1和Th 2细胞的发育中起关键作用的转录因子，SOCS（细胞因子信号传导抑制因子）家族的基因也是如此，尽管是间接的。另一种转录因子Foxp 3是天然调节性T细胞（Tcells）的主要调节因子。为了确定这些因子在未闭丝虫感染的受损Th 1应答中的作用，对丝虫感染个体（n = 6）和未感染对照（n = 6）的纯化T细胞进行细胞因子、SOCS和转录因子mRNA表达的分析。正如预期的那样（与未感染个体的细胞相反），在用寄生虫抗原（BmA）刺激后，γ干扰素（IFN-γ）显著降低，同时白细胞介素-4（IL-4）、IL-5和IL-10 mRNA表达增加，但用多克隆T细胞（抗CD 3）刺激则没有。T-bet（但不是加塔-3）在丝虫感染个体的细胞中表达水平显著低于未感染组，至少部分解释了IFN-γ表达的减少。其次，我们发现两组之间Foxp 3的表达没有显着差异，尽管Foxp 3表达的诱导与IL-10的诱导表达水平相关，表明Treg参与了所观察到的IL-10表达。最后，SOCS-1、SOCS-5和SOCS-7的寄生虫特异性T细胞表达在感染患者中显著减少;相反，SOCS-3的表达增加。因此，我们的数据表明，在专利淋巴丝虫病中观察到的受损的Th 1应答与T细胞中T-bet、SOCS-1、SOCS-5和SOCS-7的表达降低以及SOCS-3的表达增加相关。
T-bet (T-box expressed in T cells) and GATA-3 are transcription factors that play a critical role in the development of Th1 and Th2 cells, as do genes of the SOCS (suppressor of cytokine signaling) family, albeit indirectly. Another transcription factor, Foxp3, is a master regulator of natural regulatory T cells (Tregs). To identify the role of these factors in impaired Th1 responses of patent filarial infection, analysis of cytokine, SOCS, and transcription factor mRNA expression was performed on purified T cells of filaria-infected individuals (n = 6) and uninfected controls (n = 6). As expected (and in contrast to cells of uninfected individuals), there was a significant depression of gamma interferon (IFN-gamma) and a concomitant increase in interleukin-4 (IL-4), IL-5, and IL-10 mRNA expression following stimulation with parasite antigen (BmA) but not with a polyclonal T-cell (anti-CD3) stimulus. T-bet (but not GATA-3) was expressed at significantly lower levels in cells of filaria-infected individuals in response to BmA compared with those from the uninfected group, accounting, at least partially, for the diminished IFN-gamma expression. Second, we found no significant differences in expression of Foxp3 between the two groups, although induction of Foxp3 expression correlated with induced expression levels of IL-10, implicating Tregs in the IL-10 expression seen. Finally, parasite-specific T-cell expression of SOCS-1, SOCS-5, and SOCS-7 was significantly diminished among infected patients; in contrast, expression of SOCS-3 increased. Our data therefore indicate that the impaired Th1 responses observed in patent lymphatic filariasis are associated with decreased expression of T-bet, SOCS-1, SOCS-5, and SOCS-7 and increased expression of SOCS-3 in T cells.