IL-15 mediated immune programming in nonhuman primates to improve vaccine efficacy

About This Grant

ABSTRACT: Interleukin (IL)-15, a proinflammatory cytokine, has garnered significant interest for its immunotherapeutic potential, and recently for its role in mediating a protective immune response to a candidate HIV vaccine. IL-15 is a predicted upstream regulatory for the protective immune response elicited by a cytomegalovirus vector- based vaccine (RhCMV/SIV) in simian immunodeficiency virus (SIV) challenged rhesus macaques (RM), which is highly correlated with a robust whole blood transcriptional signature (wbPPTS). Modulating key pathways in the IL-15/wbPPTS signaling axis, pharmacologically or through vector engineering, may improve vaccine protective efficacy. However, our limited understanding of IL-15 signaling networks, and their connection to the wbPPTS and vaccine protection, represents a significant knowledge gap. The overall objective of this proposal is to comprehensively characterize IL-15 signaling networks in RM myeloid and lymphoid cells, and identify linkages between key networks, the wbPPTS, and vaccine protection. Studies in RM and human blood cells indicate monocytes are the major contributor to the wbPPTS after IL-15 stimulation. Other cell types that likely contribute to the IL-15-mediated wbPPTS include subpopulations of natural killer cells and cytotoxic CD8+ T-cells. The central hypothesis is IL-15 signaling activates previously undefined signaling networks in these cell populations, which are critical for RhCMV/SIV-mediated vaccine protection. This hypothesis will be tested with the following Aims: 1) Defining cell-specific IL-15 associated transcriptional networks and chromatin accessibility changes; 2) Defining cell-specific IL-15 signal transduction pathway engagement; and 3) Identifying key signaling networks associated with vaccine protection through multiomics in vitro and in vivo data integration. These studies are highly significant because they will further our understanding of IL-15 immunobiology and the RhCMV/SIV vaccine protective mechanism, as well as identify therapeutic targets for improving vaccine efficacy. The proposed Mentored Research Scientist Career Development Award will provide the necessary protected research time, training, and mentorship for Dr. Isaac Barber-Axthelm to transition into an independent investigator utilizing NHP models. As one of the top research universities with extensive resources, globally recognized faculty, and a collaborative work environment, The University of Washington is an ideal location to conduct this work. Dr. Barber-Axthelm’s career development plan builds on his background in immunology and NHP biology with coursework and training in molecular biology, bioinformatics, and systems biology. This, along with guidance from his mentors and a multidisciplinary advisory committee, will provide Dr. Barber-Axthelm with the critical knowledge, experience, and skills to develop an independent research program focused on innate signaling pathway regulation of the adaptive immune system.