Increased plasmacytoid dendritic cell maturation and natural killer cell activation in HIV-1 exposed, uninfected intravenous drug users.
Increased plasmacytoid dendritic cell maturation and natural killer cell activation in HIV-1 exposed, uninfected intravenous drug users.
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DOI：
10.1097/qad.0b013e32833dfc20
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发表时间：
2010-09-10
期刊：
影响因子：
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通讯作者：
Montaner LJ
中科院分区：
文献类型：
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作者：
Tomescu C;Duh FM;Lanier MA;Kapalko A;Mounzer KC;Martin MP;Carrington M;Metzger DS;Montaner LJ
在几个暴露于HIV-1的未感染受试者队列中，NK活化增加与HIV-1感染抵抗相关。在暴露于HIV-1的未感染受试者亚组中也观察到保护性NK受体等位基因（KIR 3DS 1和KIR 3DL 1高）的遗传。然而，在HIV-1暴露的，未感染的静脉注射吸毒者（EU-IDU）的NK细胞活化的确切机制仍有待阐明。我们研究了宿主基因型和病原体诱导的树突状细胞在高危活动期间对NK激活的调节作用，研究对象为来自费城的15名EU-IDU受试者和15名对照、未感染供体。我们通过流式细胞术评估NK细胞和树突状细胞的活化状态，并利用NK-DC串扰的功能测定来表征EU-IDU受试者中的先天免疫区室。如先前所报告，与对照未感染供体相比，EU-IDU受试者中的NK细胞活化（CD 69）和/或脱粒（CD 107 a）显著增加（p=0.0056，n=13）。基因型分析表明，在我们的EU-IDU受试者队列中，保护性KIR（KIR 3DS 1）和HLA-Bw 4 * 80 I配体的频率并不富集。相反，与对照未感染供体相比，来自EU-IDU的浆细胞样树突状细胞（PDC）表现出更高的成熟度（CD 83）（p=0.0011，n=12）。当在体外刺激时，来自EU-IDU受试者的PDC和NK细胞均保持强效应细胞功能，并且未表现出衰竭迹象。PDCs的成熟增加与EU-IDU受试者的NK活化增加相关，这表明先天区室的两个成员可能有助于EU-IDU对HIV-1感染的抵抗。
Increased NK activation has been associated with resistance to HIV-1 infection in several cohorts of HIV-1 exposed, uninfected subjects. Inheritance of protective NK receptor alleles (KIR3DS1 and KIR3DL1high) has also been observed in a subset of HIV-1 exposed, uninfected subjects. However, the exact mechanism contributing to NK activation in HIV-1 exposed, uninfected intra-venous drug users (EU-IDU) remains to be elucidated. We investigated the role of both host genotype and pathogen-induced dendritic cell modulation of NK activation during high-risk activity in a cohort of 15 EU-IDU subjects and 15 control, uninfected donors from Philadelphia. We assessed the activation status of NK cells and Dendritic cells by flow cytometry and utilized functional assays of NK-DC cross-talk to characterize the innate immune compartment in EU-IDU subjects. As previously reported, NK cell activation (CD69) and/or degranulation (CD107a) was significantly increased in EU-IDU subjects compared to control uninfected donors (p=0.0056, n=13). Genotypic analysis indicated that the frequency of protective KIR (KIR3DS1) and HLA-Bw4*80I ligands was not enriched in our cohort of EU-IDU subjects. Rather, plasmacytoid dendritic cells (PDC) from EU-IDU exhibited heightened maturation (CD83) compared to control uninfected donors (p=0.0011, n=12). When stimulated in vitro, both PDCs and NK cells from EU-IDU subjects maintained strong effector cell function and did not exhibit signs of exhaustion. Increased maturation of PDCs is associated with heightened NK activation in EU-IDU subjects suggesting that both members of the innate compartment may contribute to resistance from HIV-1 infection in EU-IDU.