Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells

作者：Leigh H. Fisher, Melissa Zinter, Sherry Stanfield-Oakley, Lindsay N. Carpp, R. Whitney Edwards, Thomas N. Denny, Zoe Moodie, Fatima Laher, Linda‐Gail Bekker, M. Juliana McElrath, Peter B. Gilbert, Lawrence Corey, Georgia D. Tomaras, Justin Pollara, Guido Ferrari · 发表于：Frontiers in Immunology · 年份：2019 · DOI：10.3389/fimmu.2019.02741 · 被引用次数：34 · 研究领域：Immune Cell Function and Interaction、HIV Research and Treatment、T-cell and B-cell Immunology

The secondary analyses for correlates of risk of infection in the RV144 HIV-1 vaccine trial implicated vaccine-induced antibody-dependent cellular cytotoxicity (ADCC) responses in the observed protection, highlighting the importance of assessing such responses in ongoing and future HIV-1 vaccine trials. However, in vitro assays that detect ADCC activity in plasma from HIV-1 infected seropositive individuals are not always effective at detecting ADCC activity in plasma from HIV-1 vaccine recipients. In vivo, ADCC-mediating antibodies must operate at the site of infection, where effector cells are recruited and activated by a local milieu of chemokines and cytokines. Based on previous findings that interleukin 15 (IL-15) secretion increases during acute HIV-1 infection and enhances NK cell-mediated cytotoxicity, we hypothesized that IL-15 pretreatment of NK effector cells could be used to improve killing of infected cells by vaccine-induced antibodies capable of mediating ADCC. Using the HIV-1 infectious molecular clone (IMC)-infected target cell assay along with plasma samples from HIV-1 vaccine recipients, we found that IL-15 treatment of NK cells improved the ability of the vaccine-induced antibodies to recruit NK cells for ADCC. Through immunophenotyping experiments, we showed that this improved killing was likely due to IL-15 mediated activation of the NK cells and higher intracellular levels of perforin and granzyme B in the IL-15 pretreated cells. We also found that usin...