Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus- and HIV-1-specific T cell responses
Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus- and HIV-1-specific T cell responses
复制标题
DOI：
10.4049/jimmunol.171.8.4320
复制
发表时间：
2003-10-15
影响因子：
4.4
通讯作者：
Koup, RA
中科院分区：
文献类型：
--
作者：
Loré, K;Betts, MR;Koup, RA
APCs，特别是树突状细胞（dc）的最佳Ag靶向和激活在疫苗开发中非常重要。在这项研究中，我们报道了不同的toll样受体（TLR）结合化合物对增强人类APCs诱导的免疫反应的作用，包括CD123（+）浆细胞样DCs （PDCs）、CD11c（+）髓样DCs （MDCs）、单核细胞和B细胞。表达TLR7和TLR9的PDCs对咪唑喹啉类药物（咪喹莫特和R-848）和CpG寡脱氧核苷酸刺激有反应，导致共刺激分子表达增强，诱导ifn - α和IL-12p70的表达。相比之下，表达TLR3、TLR4和TLR7的MDCs对poly（I:C）、LPS和咪唑喹啉类药物有应答，表型成熟，il - 12p70高产，但不产生可检测到的ifn - α。与TLR配体激活的单核细胞和B细胞或未刺激的PDCs和MDCs相比，TLR配体刺激的PDCs或MDCs暴露于CMV或HIV-1 Ags，通过效应细胞因子的产生来测量，最理想的是，TLR配体刺激的PDCs或MDCs暴露于CMV或HIV-1 Ags，增强了自身CMV和HIV-1特异性记忆T细胞反应。总之，这些数据表明，使用TLR配体靶向特定DC亚群可以增强其激活病毒特异性T细胞的能力，为合理设计TLR配体作为疫苗或免疫调节治疗的佐剂提供了信息。
Optimal Ag targeting and activation of APCs, especially dendritic cells (DCs), are important in vaccine development. In this study, we report the effects of different Toll-like receptor (TLR)-binding compounds to enhance immune responses induced by human APCs, including CD123(+) plasmacytoid DCs (PDCs), CD11c(+) myeloid DCs (MDCs), monocytes, and B cells. PDCs, which express TLR7 and TLR9, responded to imidazoquinolines (imiquimod and R-848) and to CpG oligodeoxynucleotides stimulation, resulting in enhancement in expression of costimulatory molecules and induction of IFN-alpha and IL-12p70. In contrast, MDCs, which express TLR3, TLR4, and TLR7, responded to poly(I:C), LPS, and imidazoquinolines with phenotypic maturation and high production of IL-12 p70 without producing detectable IFN-alpha. Optimally TLR ligand-stimulated PDCs or MDCs exposed to CMV or HIV-1 Ags enhanced autologous CMV- and HIV-1-specific memory T cell responses as measured by effector cytokine production compared with TLR ligand-activated monocytes and B cells or unstimulated PDCs and MDCs. Together, these data show that targeting specific DC subsets using TLR ligands can enhance their ability to activate virus-specific T cells, providing information for the rational design of TLR ligands as adjuvants for vaccines or immune modulating therapy.