Switching and loss of cellular cytokine producing capacity characterize in vivo viral infection and malignant transformation in human T- lymphotropic virus type 1 infection.
Switching and loss of cellular cytokine producing capacity characterize in vivo viral infection and malignant transformation in human T- lymphotropic virus type 1 infection.
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DOI：
10.1371/journal.ppat.1006861
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发表时间：
2018-03
期刊：
影响因子：
6.7
通讯作者：
Taylor GP
中科院分区：
文献类型：
--
作者：
Kagdi H;Demontis MA;Ramos JC;Taylor GP
成人T细胞白血病/淋巴瘤(ATL)是由慢性非恶性人类T淋巴细胞白血病病毒1型(HTLV-1)感染引起的，其特点是血浆中高水平的促炎细胞因子，而ATL则以高水平的血浆抗炎(IL-10)为特征。ATL预后不良的部分原因是疾病相关的免疫抑制。ATL细胞具有CD4+CCR4+CD26-CD7-免疫表型，但具有该免疫表型的感染细胞(‘ATL样细胞’)也存在于非恶性HTLV-1感染中。我们假设ATL样细胞和ATL细胞具有不同的细胞因子产生能力，并且在白血病发生过程中产生的细胞因子发生切换。对17例无症状携带者(ACS)、28例HTLV-1相关性脊髓病(HAM)和28例ATL患者进行了研究。ATL患者血浆IL-10浓度和产生IL-10的CD4+T细胞绝对频率均显著高于AC患者。产生IL-10的ATL细胞明显高于ATL样细胞。产生细胞因子的细胞只占ATL细胞的一小部分。克隆性分析显示，即使在ATL患者中，ATL细胞也不仅由单个显性克隆(假定为ATL细胞)组成，而且还由数十个非显性感染克隆(‘ATL样’细胞)组成。细胞因子产生细胞的频率与ATL细胞中最大克隆的相对丰度呈显著负相关，提示ATL细胞不产生细胞因子，类ATL细胞是主要的细胞因子产生细胞。与非恶性HTLV-1感染患者(经TCR分析证实由数百个非显性克隆组成)相比，ATL患者的ATL细胞(经TCR分析证实由假定的ATL和“ATL样”细胞组成)中的细胞因子mRNA的表达显著低于ATL-1感染患者的ATL细胞。此外，还证实了最大克隆的相对丰度与细胞因子mRNA表达之间的显著负相关。最后，“ATL样细胞”比非“ATL样细胞”(主要是未感染HTLV)产生更少的促炎细胞因子和更多的抗炎细胞因子。综上所述，HTLV-1感染的CD4+T细胞与细胞因子产生能力的改变有关，而显性恶性克隆性生长与细胞因子产生能力的丧失有关。在非恶性HTLV-1感染患者的血浆细胞因子谱中存在非显性克隆，在ATL患者中也存在。人类T细胞淋巴病毒1型(HTLV-1)感染CD4+T细胞与其细胞因子产生能力的改变有关，是成人T细胞白血病/淋巴瘤(ATL)和非恶性HTLV-1感染患者血浆细胞因子谱不同的原因。感染的CD4+T细胞的优势恶性克隆性生长与细胞因子产生能力的丧失有关。急性冠脉综合征、HAM和ATL患者有一个共同的细胞因子簇，其促(肿瘤坏死因子α和IL-6)和抗(IL-10)炎性细胞因子呈正相关。血浆IL-10在HAM和ATL状态下高于AC，而在促炎细胞因子方面没有差异。HAM患者血浆干扰素γ、IL-10和IL-17浓度升高，提示HAM中这些细胞因子之间存在复杂的相互作用，这在ATL中是不存在的。侵袭性ATL与惰性ATL相比，血浆促炎和抗炎细胞因子浓度升高有关。这种细胞因子图谱并不是侵袭性ATL的先兆或预测。与未感染HTLV-1的非“ATL样”细胞相比，ACS和HAM患者中的“ATL样”感染细胞具有较低的促炎细胞因子分泌和较高的抗炎细胞因子分泌。假定的ATL细胞几乎没有细胞因子的产生能力。来自非显性感染克隆的“ATL样”感染细胞不仅存在于非恶性HTLV-1感染患者中，而且在ATL患者中也存在。在非恶性HTLV-1感染患者中，ATL样细胞具有产生细胞因子的能力，并对血浆细胞因子谱有贡献，可能在ATL中也是如此。
Adult T-cell leukaemia/lymphoma (ATL) arises from chronic non-malignant human T lymphotropic virus type-1 (HTLV-1) infection which is characterized by high plasma pro-inflammatory cytokines whereas ATL is characterized by high plasma anti-inflammatory (IL-10) concentrations. The poor prognosis of ATL is partly ascribed to disease-associated immune suppression. ATL cells have a CD4+CCR4+CD26-CD7- immunophenotype but infected cells with this immunophenotype (‘ATL-like’ cells) are also present in non-malignant HTLV-1 infection. We hypothesized that ‘ATL-like’ and ATL cells have distinct cytokine producing capacity and a switch in the cytokines produced occurs during leukemogenesis. Seventeen asymptomatic carriers (ACs), 28 patients with HTLV-1-associated myelopathy (HAM) and 28 with ATL were studied. Plasma IL-10 concentration and the absolute frequency of IL-10-producing CD4+ T cells were significantly higher in patients with ATL compared to AC. IL-10-producing ATL cells were significantly more frequent than ‘ATL-like’ cells. The cytokine-producing cells were only a small fraction of ATL cells. Clonality analysis revealed that even in patients with ATL the ATL cells were composed not only of a single dominant clone (putative ATL cells) but also tens of non-dominant infected clones (‘ATL-like’ cells). The frequency of cytokine-producing cells showed a strong inverse correlation with the relative abundance of the largest clone in ATL cells suggesting that the putative ATL cells were cytokine non-producing and that the ‘ATL-like’ cells were the primary cytokine producers. These findings were confirmed by RNAseq with cytokine mRNA expression in ATL cells in patients with ATL (confirmed to be composed of both putative ATL and ‘ATL-like’ cells by TCR analysis) significantly lower compared to ‘ATL-like’ cells in patients with non-malignant HTLV-1 infection (confirmed to be composed of hundreds of non-dominant clones by TCR analysis). A significant inverse correlation between the relative abundance of the largest clone and cytokine mRNA expression was also confirmed. Finally, ‘ATL-like’ cells produced less pro- and more anti-inflammatory cytokines than non ‘ATL-like’ CD4+ cells (which are predominantly HTLV uninfected). In summary, HTLV-1 infection of CD4+ T cells is associated with a change in cytokine producing capacity and dominant malignant clonal growth is associated with loss of cytokine producing capacity. Non-dominant clones with ‘ATL-like’ cells contribute to plasma cytokine profile in patients with non-malignant HTLV-1 infection and are also present in patient with ATL. Human T-cell lymphotropic virus type-1 (HTLV-1) infection of CD4+ T cells is associated with a change in their cytokine producing capacity and is responsible for the different plasma cytokine profiles in patients with adult T-cell leukaemia/Lymphoma (ATL) and non-malignant HTLV-1 infection. Dominant malignant clonal growth of the infected CD4+ T cells is associated with loss of cytokine producing capacity. ACs, patients with HAM and patients with ATL have a common cytokine cluster with positive correlations between pro- (TNFα and IL-6) and anti- (IL-10) inflammatory cytokines. Plasma IL-10 was higher in the HAM and ATL states compared to AC whilst there was no difference in pro-inflammatory cytokines. Patients with HAM have raised plasma concentrations of IFNγ, IL-10 and IL-17 suggesting a complex interaction between these cytokine in HAM which was not seen in ATL. Aggressive ATL is associated with raised plasma concentrations of pro- and anti-inflammatory cytokines compared to indolent ATL. This cytokine profile did not precede or predict aggressive ATL. The ‘ATL-like’ infected cells in ACs and in patients with HAM have lower pro- and higher anti-inflammatory cytokine secretion than non- ‘ATL-like’ cells which are predominantly HTLV-1 uninfected. Putative ATL cells have little or no cytokine producing capacity. ‘ATL-like’ infected cells from non-dominant infected clones were present not only in patients with non-malignant HTLV-1 infection but also ATL. ‘ATL-like’ cells have cytokine producing capacity and contribute to plasma cytokine profile in patients with non-malignant HTLV-1 infection and possibly also in ATL.
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影响因子：
4.6
作者：
Espindola, Otavio M.;Oliveira, Lua C.;Andrada-Serpa, Maria Jose
通讯作者：
Andrada-Serpa, Maria Jose
影响因子：
10.1
作者：
Hodson, Andrew;Laydon, Daniel J.;Taylor, Graham P.
通讯作者：
Taylor, Graham P.
影响因子：
1.5
作者：
Demontis, Maria A.;Hilburn, Silva;Taylor, Graham P.
通讯作者：
Taylor, Graham P.
影响因子：
3.3
作者：
Furuya, T;Nakamura, T;Eguchi, K
通讯作者：
Eguchi, K
影响因子：
4.4
作者：
Imai, T;Nagira, M;Yoshie, O
通讯作者：
Yoshie, O