Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques.
Date
2023-01
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
Abstract
Rhesus macaques (RMs) are a common pre-clinical model used to test HIV vaccine efficacy and passive immunization strategies. Yet, it remains unclear to what extent the Fc-Fc receptor (FcR) interactions impacting antiviral activities of antibodies in RMs recapitulate those in humans. Here, we evaluated the FcR-related functionality of natural killer cells (NKs) from peripheral blood of uninfected humans and RMs to identify intra- and inter-species variation. NKs were screened for FcγRIIIa (human) and FcγRIII (RM) genotypes (FcγRIII(a)), receptor signaling, and antibody-dependent cellular cytotoxicity (ADCC), the latter mediated by a cocktail of monoclonal IgG1 antibodies with human or RM Fc. FcγRIII(a) genetic polymorphisms alone did not explain differences in NK effector functionality in either species cohort. Using the same parameters, hierarchical clustering separated each species into two clusters. Importantly, in principal components analyses, ADCC magnitude, NK contribution to ADCC, FcγRIII(a) cell-surface expression, and frequency of phosphorylated CD3ζ NK cells all contributed similarly to the first principal component within each species, demonstrating the importance of measuring multiple facets of NK cell function. Although ADCC potency was similar between species, we detected significant differences in frequencies of NK cells and pCD3ζ+ cells, level of cell-surface FcγRIII(a) expression, and NK-mediated ADCC (P<0.001), indicating that a combination of Fc-FcR parameters contribute to overall inter-species functional differences. These data strongly support the importance of multi-parameter analyses of Fc-FcR NK-mediated functions when evaluating efficacy of passive and active immunizations in pre- and clinical trials and identifying correlates of protection. The results also suggest that pre-screening animals for multiple FcR-mediated NK function would ensure even distribution of animals among treatment groups in future preclinical trials.
Type
Department
Description
Provenance
Citation
Permalink
Published Version (Please cite this version)
Publication Info
Tuyishime, Marina, Rachel L Spreng, Brady Hueber, Junsuke Nohara, Derrick Goodman, Cliburn Chan, Richard Barfield, Whitney E Beck, et al. (2023). Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques. Frontiers in immunology, 14. p. 1260377. 10.3389/fimmu.2023.1260377 Retrieved from https://hdl.handle.net/10161/29659.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
Scholars@Duke
Thomas Norton Denny
Thomas N. Denny, MSc, M.Phil, is the Chief Operating Officer of the Duke Human Vaccine Institute (DHVI), Associate Dean for Duke Research and Discovery @RTP, and a Professor of Medicine in the Department of Medicine at Duke University Medical Center. He is also an Affiliate Member of the Duke Global Health Institute. Previously, he served on the Health Sector Advisory Council of the Duke University Fuquay School of Business. Prior to joining Duke, he was an Associate Professor of Pathology, Laboratory Medicine and Pediatrics, Associate Professor of Preventive Medicine and Community Health and Assistant Dean for Research in Health Policy at the New Jersey Medical School, Newark, New Jersey. He has served on numerous committees for the NIH over the last two decades and currently is the principal investigator of an NIH portfolio in excess of 65 million dollars. Mr. Denny was a 2002-2003 Robert Wood Johnson Foundation Health Policy Fellow at the Institute of Medicine of the National Academies (IOM). As a fellow, he served on the US Senate Health, Education, Labor and Pensions Committee with legislation/policy responsibilities in global AIDS, bioterrorism, clinical trials/human subject protection and vaccine related-issues.
As the Chief Operating Officer of the DHVI, Mr. Denny has senior oversight of the DHVI research portfolio and the units/teams that support the DHVI mission. He has extensive international experience and previously was a consultant to the U.S. Centers for Disease Control and Prevention (CDC) for the President’s Emergency Plan for AIDS Relief (PEPFAR) project to oversee the development of an HIV and Public Health Center of Excellence laboratory network in Guyana. In September 2004, the IOM appointed him as a consultant to their Board on Global Health Committee studying the options for overseas placement of U.S. health professionals and the development of an assessment plan for activities related to the 2003 PEPFAR legislative act. In the 1980s, Mr. Denny helped establish a small laboratory in the Republic of Kalmykia (former Soviet Union) to improve the care of children with HIV/AIDS and served as a Board Member of the Children of Chernobyl Relief Fund Foundation. In 2005, Mr. Denny was named a consulting medical/scientific officer to the WHO Global AIDS Program in Geneva. He has also served as program reviewers for the governments of the Netherlands and South Africa as well as an advisor to several U.S. biotech companies. He currently serves as the Chair of the Scientific Advisory Board for Grid Biosciences.
Mr. Denny has authored and co-authored more than 200 peer-reviewed papers and serves on the editorial board of Communications in Cytometry and Journal of Clinical Virology. He holds an M.Sc in Molecular and Biomedical Immunology from the University of East London and a degree in Medical Law (M.Phil) from the Institute of Law and Ethics in Medicine, School of Law, University of Glasgow. In 1991, he completed a course of study in Strategic Management at The Wharton School, University of Pennsylvania. In 1993, he completed the Program for Advanced Training in Biomedical Research Management at Harvard School of Public Health. In December 2005, he was inducted as a Fellow into the College of Physicians of Philadelphia, the oldest medical society in the US.
While living in New Jersey, Mr. Denny was active in his community, gaining additional experience from two publicly elected positions. In 2000, Mr. Denny was selected by the New Jersey League of Municipalities to Chair the New Jersey Community Mental Health Citizens’ Advisory Board and Mental Health Planning Council as a gubernatorial appointment.
Michael Anthony Moody
Tony Moody, MD is a Professor in the Department of Pediatrics, Division of Infectious Diseases and Professor in the Department of Integrative Immunobiology at Duke University Medical Center. Research in the Moody lab is focused on understanding the B cell responses during infection, vaccination, and disease. The lab has become a resource for human phenotyping, flow characterization, staining and analysis at the Duke Human Vaccine Institute (DHVI). The Moody lab is currently funded to study influenza, syphilis, HIV-1, and emerging infectious diseases.
Dr. Moody is the director of the Duke CIVICs Vaccine Center (DCVC) at (DHVI) and co-director of the Centers for Research of Emerging Infectious Disease Coordinating Center (CREID-CC). Dr. Moody is mPI of a U01 program to develop a syphilis vaccine; this program is a collaboration with mPI Dr. Justin Radolf at the University of Connecticut. Dr. Moody is also the director of the DHVI Accessioning Unit, a biorepository that provides support for work occurring at DHVI and with its many collaborators around the world by providing processing, shipping, and inventory support for a wide array of projects.
Dr. Moody and his team are involved in many networks studying vaccine response including the Collaborative Influenza Vaccine Innovation Centers (CIVICs) and the COVID-19 Prevention Network (CoVPN).
Georgia Doris Tomaras
Dr. Georgia Tomaras is a tenured Professor of Surgery, Professor of Immunology, Professor of Molecular Genetics and Microbiology and is a Fellow of the American Academy of Microbiology (AAM) and a Fellow of the American Association for the Advancement of Science (AAAS). Dr. Tomaras is Co-Director of the Center for Human Systems Immunology (CHSI) Duke University and Director of the Duke Center for AIDS Research (CFAR). Her national and international leadership roles include: Executive Management Team (EMT) leader and mPI for the HIV Vaccine Trials Network (HVTN); Director of Lab Sciences (HVTN); and Chair of NIH Vaccine Research Center (VRC) Board of Scientific Counselors. Her prior leadership roles include serving as the Director of Research, Duke Human Vaccine Institute (DHVI); Director of the DHVI Training Program; Associate Director of DHVI Research; Co-Director of the Interdisciplinary Research Training Program in AIDS (IRTPA) Duke; Chair of the National Institutes of Health (NIH) AIDS Vaccine Research Subcommittee (AVRS), and Advisory Counsel member of the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID). Dr. Tomaras’ primary research focus is deciphering mechanisms of protective human immunity and identification of immune correlates of protection to further development of effective vaccines against infectious diseases.
Roger Keith Reeves
Formerly of Harvard Medical School and Beth Israel Deaconess Medical Center, Dr. R. Keith Reeves is currently tenured Professor of Surgery at Duke University, as well as Director of the Division of Innate and Comparative Immunology and Head of Innovation Partnerships in the Center for Human Systems Immunology. He is also currently the Director of the Duke CFAR Developmental Core and Editor-in-Chief of AIDS Research and Human Retroviruses. Over his academic career he has published extensively in the field of NK cell biology, providing some of the most comprehensive analyses of NK cells and innate lymphoid cells, including the first characterization of memory NK cells in any primate species. Dr. Reeves’ research has been supported by NIH for over a decade by individual and consortia grants, and in addition to independent work, he collaborates as part of the HIV Vaccine Trials Network (HVTN) and the BEAT-HIV Martin Delaney HIV Cure Collaboratory. Dr. Reeves has also served on multiple standing NIH study sections (HIV Immunopathogenesis and Vaccine Development), as well as on standing and ad hoc grant review committees for amfAR, the United States-Israel Binational Science Foundation, the UK Medical Research Council and California Institute of Regenerative Medicine, among others. Considered a global expert in NK cell biology, Dr. Reeves’ group continues to focus on cutting edge approaches to harness NK cells in the context of vaccines and antiviral therapeutics for HIV, CMV, HCV, influenza and SARSCoV2.
Guido Ferrari
The activities of the Ferrari Laboratory are based on both independent basic research and immune monitoring studies. The research revolves around three main areas of interest: class I-mediated cytotoxic CD8+ T cell responses, antibody-dependent cellular cytotoxicity (ADCC), gene expression in NK and T cellular subsets upon infection with HIV-1. With continuous funding over the last 11 years from the NIH and Bill & Melinda Gates Foundation along with many other productive collaborations within and outside of Duke, the Ferrari Lab has expanded its focus of research to include the ontogeny of HIV-1 specific immune responses that work by eliminating HIV-1 infected cells and how these can be induced by AIDS vaccine candidates.
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.