Marin-Esteban Viviana, Abdul Mubashira, Charron Dominique, Haziot Alain, Mooney Nuala
Institut National de la Santé et de la Recherche Médicale U662, Paris, France.
Clin Vaccine Immunol. 2008 Jun;15(6):954-62. doi: 10.1128/CVI.00428-07. Epub 2008 Apr 9.
Monocyte-derived dendritic cells (DCs) differentiate in the presence of Toll-like-receptor (TLR) ligands in the course of ongoing infections. A single-stranded RNA (ssRNA) sequence, corresponding to the sequence of the U5 region of human immunodeficiency virus type 1 RNA, was used to mimic viral activation of TLR7 in human DCs. We determined the effector potential of DCs differentiated in the presence of this ssRNA molecule (ssRNA-DCs). ssRNA-DCs phenotypically resembled mature DCs. In contrast, their capacity to allostimulate naive CD4(+) T cells resembled that of conventional immature DCs and could be increased by TLR4 stimulation. Th1 polarization of CD4(+) T cells and production of interleukin 12p70 (IL-12p70) by ssRNA-DCs were selectively abrogated in response to a late TLR4, but not in response to a CD40, maturation signal. Inhibition of p38 mitogen-activated protein kinase partially restored IL-12p70 secretion but did not restore Th1 polarization, whereas addition of exogenous IL-12 led to recovery of Th1 polarization. In contrast to lipopolysaccharide, ssRNA induced IL-12p70 production at the very earliest stages of DC differentiation, indicating a particular role for TLR7 in monocyte-derived DCs recently engaged in differentiation. These data demonstrate generation of phenotypically mature DCs with the ability to expand CD4(+) T lymphocytes lacking Th1/2-polarizing capacity.
在持续感染过程中,单核细胞来源的树突状细胞(DCs)在Toll样受体(TLR)配体存在的情况下发生分化。一段与人类免疫缺陷病毒1型RNA的U5区域序列相对应的单链RNA(ssRNA)序列,被用于模拟人类DCs中TLR7的病毒激活。我们确定了在这种ssRNA分子(ssRNA-DCs)存在下分化的DCs的效应潜能。ssRNA-DCs在表型上类似于成熟DCs。相比之下,它们对幼稚CD4(+) T细胞的同种异体刺激能力类似于传统未成熟DCs,并且可通过TLR4刺激而增强。ssRNA-DCs对CD4(+) T细胞的Th1极化和白细胞介素12p70(IL-12p70)的产生,在响应晚期TLR4成熟信号时被选择性地消除,但对CD40成熟信号则无此反应。抑制p38丝裂原活化蛋白激酶可部分恢复IL-12p70的分泌,但不能恢复Th1极化,而添加外源性IL-12可导致Th1极化的恢复。与脂多糖不同,ssRNA在DC分化的最早阶段就诱导IL-12p70的产生,表明TLR7在最近参与分化的单核细胞来源的DCs中具有特殊作用。这些数据证明了产生了表型成熟的DCs,其具有扩增缺乏Th1/2极化能力的CD4(+) T淋巴细胞的能力。