Cattedra di Immunologia, Università degli Studi di Milano, Milan, Italy.
J Immunol. 2010 Mar 1;184(5):2710-7. doi: 10.4049/jimmunol.0902463. Epub 2010 Feb 1.
TLRs trigger innate immunity that recognizes conserved motifs of invading pathogens, resulting in cellular activation and release of inflammatory factors. The influence of TLR activation on resistance to HIV-1 infection has not been investigated in HIV-1 exposed seronegative (ESN) individuals. PBMCs isolated from heterosexually ESN individuals were stimulated with agonists specific for TLR3 (poly I:C), TLR4 (LPS), TLR7 (imiquimod), and TLR7/8 (ssRNA40). We evaluated expression of factors involved in TLR signaling cascades, production of downstream effector immune mediators, and TLR-expression in CD4+ and CD14+ cells. Results were compared with those obtained in healthy controls (HCs). ESN individuals showed: 1) comparable percentages of CD14+/TLR4+ and CD4+/TLR8+ CD14+/TLR8+ cells; 2) higher responsiveness to poly I:C, LPS, imiquimod, and ssRNA40 stimulation, associated with significantly increased production of IL-1beta, IL-6, TNF-alpha, and CCL3; 3) augmented expression of mRNA specific for other targets (CCL2, CSF3, CSF2, IL-1alpha, IL-8, IL-10, IL-12, cyclooxygenase 2) demonstrated by broader TLRs pathway expression analyses; and 4) increased MyD88/MyD88s(short) ratio, mainly following TLR7/8 stimulation. We also compared TLR-agonist-stimulated cytokine/chemokine production in CD14+ PBMCs and observed decreased IFN-beta production in ESN individuals compared with HCs upon TLR7/8-agonist stimulation. These data suggest that TLR stimulation in ESN individuals results in a more robust release of immunologic factors that can influence the induction of stronger adaptive antiviral immune responses and might represent a virus-exposure-induced innate immune protective phenotype against HIV-1.
TLRs 触发先天免疫，识别入侵病原体的保守基序，导致细胞激活和炎症因子释放。TLR 激活对 HIV-1 感染的抵抗力的影响尚未在 HIV-1 暴露但血清阴性（ESN）个体中进行研究。从异性恋 ESN 个体中分离出的 PBMC 用 TLR3（多聚 I：C）、TLR4（LPS）、TLR7（咪喹莫特）和 TLR7/8（ssRNA40）的激动剂刺激。我们评估了参与 TLR 信号级联的因子的表达、下游效应免疫介质的产生以及 CD4+和 CD14+细胞中的 TLR 表达。结果与健康对照（HC）进行了比较。ESN 个体表现出：1）CD14+/TLR4+和 CD4+/TLR8+CD14+/TLR8+细胞的百分比相当；2）对多聚 I：C、LPS、咪喹莫特和 ssRNA40 刺激的反应性更高，与 IL-1beta、IL-6、TNF-alpha 和 CCL3 的产量显著增加相关；3）通过更广泛的 TLRs 途径表达分析，显示其他靶标（CCL2、CSF3、CSF2、IL-1alpha、IL-8、IL-10、IL-12、环加氧酶 2）的 mRNA 特异性表达增加；和 4）MyD88/MyD88s(short) 比率增加，主要是在 TLR7/8 刺激后。我们还比较了 CD14+PBMC 中 TLR 激动剂刺激的细胞因子/趋化因子产生，并观察到 ESN 个体在 TLR7/8 激动剂刺激时 IFN-beta 产生减少与 HCs 相比。这些数据表明，ESN 个体中的 TLR 刺激导致更强烈的免疫因子释放，这可能影响更强的适应性抗病毒免疫反应的诱导，并可能代表针对 HIV-1 的病毒暴露诱导的先天免疫保护表型。
