Wilson C C, Olson W C, Tuting T, Rinaldo C R, Lotze M T, Storkus W J
Departments ofInternal Medicine, Surgery, Infectious Diseases and Microbiology, University of Pittsburgh School of Medicine, Pennsylvania, USA.
J Immunol. 1999 Mar 1;162(5):3070-8.
Vaccine strategies designed to elicit strong cell-mediated immune responses to HIV Ags are likely to lead to protective immunity against HIV infection. Dendritic cells (DC) are the most potent APCs capable of priming both MHC class I- and II-restricted, Ag-specific T cell responses. Utilizing a system in which cultured DC from HIV-seronegative donors were used as APC to present HIV-1 Ags to autologous T cells in vitro, the strength and specificity of primary HIV-specific CTL responses generated to exogenous HIV-1 Nef protein as well as intracellularly expressed nef transgene product were investigated. DC expressing the nef gene were able to stimulate Nef-specific CTL, with T cells from several donors recognizing more than one epitope restricted by a single HLA molecule. Primary Nef-specific CTL responses were also generated in vitro using DC pulsed with Nef protein. T cells primed with Nef-expressing DC (via protein or transgene) were able to lyse MHC class I-matched target cells pulsed with defined Nef epitope peptides as well as newly identified peptide epitopes. The addition of Th1-biasing cytokines IL-12 or IFN-alpha, during priming with Nef-expressing DC, enhanced the Nef-specific CTL responses generated using either Ag-loading approach. These results suggest that this in vitro vaccine model may be useful in identifying immunogenic epitopes as vaccine targets and in evaluating the effects of cytokines and other adjuvants on Ag-specific T cell induction. Successful approaches may provide information important to the development of prophylactic HIV vaccines and are envisioned to be readily translated into clinical DC-based therapeutic vaccines for HIV-1.
旨在引发针对HIV抗原的强烈细胞介导免疫反应的疫苗策略可能会产生针对HIV感染的保护性免疫。树突状细胞（DC）是最有效的抗原呈递细胞，能够启动MHC I类和II类限制性的、抗原特异性T细胞反应。利用一个系统，其中来自HIV血清阴性供体的培养DC被用作抗原呈递细胞，在体外将HIV-1抗原呈递给自体T细胞，研究了对外源HIV-1 Nef蛋白以及细胞内表达的nef转基因产物产生的原发性HIV特异性CTL反应的强度和特异性。表达nef基因的DC能够刺激Nef特异性CTL，来自几个供体的T细胞识别受单个HLA分子限制的多个表位。使用用Nef蛋白脉冲的DC在体外也产生了原发性Nef特异性CTL反应。用表达Nef的DC（通过蛋白质或转基因）启动的T细胞能够裂解用确定的Nef表位肽以及新鉴定的肽表位脉冲的MHC I类匹配靶细胞。在用表达Nef的DC启动期间添加偏向Th1的细胞因子IL-12或IFN-α，增强了使用任何一种抗原加载方法产生的Nef特异性CTL反应。这些结果表明，这种体外疫苗模型可能有助于鉴定作为疫苗靶点的免疫原性表位，并评估细胞因子和其他佐剂对抗原特异性T细胞诱导的影响。成功的方法可能会为预防性HIV疫苗的开发提供重要信息，并有望很容易地转化为基于DC的HIV-1临床治疗性疫苗。
