Loré Karin, Betts Michael R, Brenchley Jason M, Kuruppu Janaki, Khojasteh Soorena, Perfetto Stephen, Roederer Mario, Seder Robert A, Koup Richard A
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3022, USA.
J Immunol. 2003 Oct 15;171(8):4320-8. doi: 10.4049/jimmunol.171.8.4320.
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.
最佳的抗原靶向和抗原呈递细胞（尤其是树突状细胞，即DCs）的激活在疫苗开发中至关重要。在本研究中，我们报告了不同的Toll样受体（TLR）结合化合物对增强人抗原呈递细胞诱导的免疫反应的影响，这些抗原呈递细胞包括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对咪唑喹啉类化合物（咪喹莫特和R-848）以及CpG寡脱氧核苷酸刺激有反应，导致共刺激分子表达增强以及IFN-α和IL-12p70的诱导。相比之下，表达TLR3、TLR4和TLR7的mDCs对聚肌苷酸:聚胞苷酸（poly(I:C)）、脂多糖（LPS）和咪唑喹啉类化合物有反应，表现为表型成熟和IL-12 p70的高产量，且不产生可检测到的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，用最佳TLR配体刺激的pDCs或mDCs暴露于巨细胞病毒（CMV）或HIV-1抗原时，通过效应细胞因子产生测量，增强了自体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配体靶向特定的DC亚群可以增强它们激活病毒特异性T细胞的能力，为合理设计TLR配体作为疫苗佐剂或免疫调节疗法提供了信息。
