ManfrereC Kelly C G, Torrealba Marina P, Miyashiro Denis R, Pereira Nátalli Z, Yoshikawa Fabio S Y, de M Oliveira Luana, Cury-Martins Jade, Duarte Alberto J S, Sanches José A, Sato Maria N
Laboratory of Medical Investigation, LIM-56, Department of Dermatology, Tropical Medicine Institute of São Paulo, University of São Paulo Medical School, São Paulo, Brazil.
Cutaneous Lymphoma Clinic, Hospital das Clínicas, Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil.
Oncotarget. 2017 Sep 18;8(54):92183-92194. doi: 10.18632/oncotarget.21006. eCollection 2017 Nov 3.
Sézary syndrome (SS), an aggressive and leukemic form of cutaneous T-cell lymphoma, usually results in shortened survival. Improving innate immunity in SS by targeting natural killer (NK) cells with Toll-like receptor (TLR) agonists could be an interesting modulatory strategy. We evaluated the NK cell populations in SS patients assessing activating and inhibitory receptors expression and profiled the differential expression of TLR signaling pathway genes in unstimulated NK cells and after TLR7/8 stimulation. We observed preserved CD56 NK cells and a low percentage of CD56 NK cells in the peripheral blood of SS patients compared to those in the healthy control group. Both NK cell populations showed down-modulation of NKG2C and NKG2D expression, which was associated with high serum levels of the soluble form of NKG2D ligands. In contrast, an expansion of "memory" CD57+ NKG2C+ NK cells and high cytomegalovirus antibody titers were detected in SS patients. Profiling of the TLR signaling genes in NK cells from SS patients showed an abundance of differentially expressed genes (DEGs) in NK cells in the unstimulated condition, with mostly up-regulation of NFκB/JNK p38 pathway genes, but there was down-regulation of type I (IFN-α/β) and II (IFN-γ) interferon and IL-12A. After activation of NK cells with TLR7/8 agonist, the down-regulated genes correlated with the IFN response, and IL-12 became up-regulated, together with other antitumor factors. NK cell activation with a dual agonist for TLR7 and TLR8 is able to induce the expression of IFN-γ and type I IFN, which can improve immunity in SS patients.
塞扎里综合征（SS）是一种侵袭性的皮肤T细胞淋巴瘤白血病形式，通常会导致生存期缩短。通过用Toll样受体（TLR）激动剂靶向自然杀伤（NK）细胞来改善SS患者的先天免疫可能是一种有趣的调节策略。我们评估了SS患者的NK细胞群体，评估了激活和抑制性受体的表达，并分析了未刺激的NK细胞以及TLR7/8刺激后TLR信号通路基因的差异表达。我们观察到，与健康对照组相比，SS患者外周血中CD56⁺NK细胞数量保留，但CD56⁻NK细胞比例较低。两个NK细胞群体均显示NKG2C和NKG2D表达下调，这与NKG2D配体可溶性形式的高血清水平相关。相反，在SS患者中检测到“记忆”CD57⁺NKG2C⁺NK细胞扩增和高巨细胞病毒抗体滴度。对SS患者NK细胞中TLR信号基因的分析显示，在未刺激条件下NK细胞中有大量差异表达基因（DEG），NFκB/JNK p38通路基因大多上调，但I型（IFN-α/β）和II型（IFN-γ）干扰素以及IL-12A下调。用TLR7/8激动剂激活NK细胞后，下调的基因与IFN反应相关，IL-12与其他抗肿瘤因子一起上调。用TLR7和TLR8双重激动剂激活NK细胞能够诱导IFN-γ和I型IFN的表达，从而改善SS患者的免疫力。
