Serghides Lena, Bukczynski Jacob, Wen Tao, Wang Chao, Routy Jean-Pierre, Boulassel Mohamed-Rachid, Sekaly Rafick-Pierre, Ostrowski Mario, Bernard Nicole F, Watts Tania H
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
J Immunol. 2005 Nov 15;175(10):6368-77. doi: 10.4049/jimmunol.175.10.6368.
CTL are important effectors of antiviral immunity. Designing adjuvants that can induce strong cytotoxic T cell responses in humans would greatly improve the effectiveness of an antiviral vaccination or therapeutic strategy. Recent evidence suggests that, in addition to its well-established role in costimulation of CD4 T cell responses, OX40L (CD134) can directly costimulate mouse CD8 T cells. In this study, we evaluated the role of OX40L in costimulation of human antiviral CD8 T cell responses and compared it with two other important costimulators, B7.1 (CD80) and 4-1BBL (CD137L). Delivery of OX40L to human monocytes using a recombinant replication-defective adenovirus led to greater expansion, up-regulation of perforin, enhanced cytolytic activity, and increased numbers of IFN-gamma- and TNF-alpha-producing antiviral memory CD8 T cells in cultures of total T cells. Synergistic or additive effects were observed when OX40L costimulation was combined with 4-1BBL (CD137L) or B7.1 (CD80) costimulation. In total T cell cultures, at low Ag dose, 4-1BBL provided the most potent costimulus for influenza-specific CD8 T cell expansion, followed by B7.1 (CD80) and then OX40L. For isolated CD8 T cells, 4-1BBL was also the most consistent costimulator, followed by B7.1. In contrast, OX40L showed efficacy in direct activation of memory CD8 T cells in only one of seven donors. Thus, OX40L costimulates human antiviral memory CD8 T cell responses largely through indirect effects and can enhance anti-influenza, anti-EBV, and anti-HIV responses, particularly in combination with 4-1BBL or B7.
细胞毒性T淋巴细胞（CTL）是抗病毒免疫的重要效应细胞。设计能够在人类中诱导强烈细胞毒性T细胞反应的佐剂，将极大地提高抗病毒疫苗接种或治疗策略的有效性。最近的证据表明，除了其在共刺激CD4 T细胞反应中已确立的作用外，OX40L（CD134）还可以直接共刺激小鼠CD8 T细胞。在本研究中，我们评估了OX40L在共刺激人类抗病毒CD8 T细胞反应中的作用，并将其与另外两种重要的共刺激分子B7.1（CD80）和4-1BBL（CD137L）进行了比较。使用重组复制缺陷型腺病毒将OX40L递送至人单核细胞，导致在总T细胞培养物中更大程度的扩增、穿孔素上调、细胞溶解活性增强以及产生干扰素-γ和肿瘤坏死因子-α的抗病毒记忆CD8 T细胞数量增加。当OX40L共刺激与4-1BBL（CD137L）或B7.1（CD80）共刺激联合使用时，观察到协同或相加效应。在总T细胞培养物中，在低抗原剂量下，4-1BBL为流感特异性CD8 T细胞扩增提供了最有效的共刺激，其次是B7.1（CD80），然后是OX40L。对于分离的CD8 T细胞，4-1BBL也是最一致的共刺激分子，其次是B7.1。相比之下，OX40L仅在七名供体中的一名中显示出对记忆CD8 T细胞的直接激活功效。因此，OX40L主要通过间接作用共刺激人类抗病毒记忆CD8 T细胞反应，并可增强抗流感、抗EBV和抗HIV反应，特别是与4-1BBL或B7联合使用时。
