Warren J. Leonard, MD, NIH Distinguished Investigator, Chief, Laboratory of Molecular Immunology, and Director, Immunology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, USA
The ICIS Awards Committee has chosen Warren J. Leonard, MD as the recipient of the 2020 Seymour & Vivian Milstein Award for Excellence in Interferon and Cytokine Research in recognition of his ground breaking scientific contributions in both the basic biology of cytokine signaling (particularly IL-2 and related cytokines) and translational aspects, where he performed pioneering work in the area of X-linked severe combined immunodeficiency. His work continues to explore the role of cytokines in immune dysregulation.
Dr. Leonard is a physician-scientist whose contributions represent the “pinnacle of scientific achievement in interferon and cytokine research”. He has made outstanding contributions in both basic science and translational areas, with many of his contributions being notable for innovation, creativity, and the potential for clinical application.
His ground-breaking scientific contributions in the area of cytokines began in the early 1980’s when he cloned the IL-2 receptor α chain (IL-2Rα). After cloning IL-2Rα, he went on to co-discover IL-2Rβ and then in a truly transformative study demonstrated that mutations in the IL2RG gene (encoding IL-2Rγ) cause X-linked severe combined immunodeficiency (XSCID, also known as the “Bubble Boy” disease) and then discovered that multiple cytokines share IL-2Rγ, leading him to rename IL-2Rγ as the common cytokine receptor γ chain (γc) and to name these cytokines as the γc family of cytokines. He also discovered additional forms of human SCID (JAK3-deficient SCID, and IL7R-deficient SCID) that result from defective cytokine signaling, co-discovered the IL-21 receptor, and over the years has performed a remarkable range of studies related to γc family cytokines, spanning their biology, signaling, gene regulation, and epigenetics, with exciting more recent studies on novel IL-2 partial agonists and super-enhancers.
Leonard’s finding the genetic basis for these forms of human inherited immunodeficiency were milestone discoveries, establishing that they were distinct diseases and allowing precise molecular diagnosis. Moreover, Leonard’s group established proof of principle in curing “XSCID mice” by gene therapy, paving the way to subsequent human gene therapy by Alain Fischer. Furthermore, in his paper describing human JAK3-deficient SCID, Leonard hypothesized that JAK3 inhibitors would be immunosuppressive, providing scientific rationale for the development of such agents, such as Pfizer’s tofacitinib, which is now a major medication for rheumatoid arthritis and other diseases. Because XSCID, JAK3-deficient SCID, and IL7R-deficient SCID account for over half of all human XSCID, Leonard’s contributions have impacted more SCID patients than the work of all other investigators in the world combined related to allowing precise genetic diagnosis of SCID. Moreover, his Il2rg-deficient mice were used to create NSG mice, which are extensively used worldwide in tumor models.
Over the years, Leonard has continued to make extraordinary contributions spanning from basic science to important translational studies, summarized as follows:
- He cloned the IL-21 receptor with colleagues at SmithKline, pioneering and helping shape the field along with investigators from Zymogenetics
- To identify the biological role of key cytokines and their receptors, Leonard’s group has made many critical knockout and transgenic mice and tremendously increased our understanding of the biology of these systems.
- His group also showed that IL-21 promotes the development of multiple forms of autoimmune disease, including type I diabetes and autoimmune uveitis.
- He was a pioneer in applying ChIP-Seq methodology to STAT proteins in T cells and discovered a genome-wide cooperation of STAT3 and IRF4, which represented a new STAT-IRF association. His group then co-discovered AP1-IRF4 consensus elements (AICEs) and demonstrated that they were key regulators of IL-21 signaling in T cells.
- More recently he demonstrated a complex interplay between IL-21 and type I interferons related to the clearance of methicillin resistantaureusand in other seminal work with Luca Gattinoni, his group compared the metabolic effects of IL-2 and IL-21 and elucidated mechanisms for enhanced antitumor efficacy in adoptive T cell immunotherapy.
- He identified a role for TSLP in allergic inflammation in the lung and discovered that TSLP activates Janus family tyrosine kinases JAK l/JAK2, thereby overturning the prevailing dogma that TSLP did not activate JAK kinases.
- He was the first to establish the significance of STAT tetramerization in vivo. His group generated Stat5a/Stat5bdouble knockin mice and discovered critical roles for STAT5 tetramerization for IL-2-induced T cell proliferation as well as for the development of and sustaining normal NK cell numbers.
- He then teamed with K. Christopher Garcia’s laboratory at Stanford University, to study novel partial agonists of IL-2– the first partial agonists for a type I cytokine, to demonstrate that engineered cytokine partial agonists were new ways to fine-tune cytokine signals. These studies included the analysis of a potent antagonist of IL-2 that his group showed is an inhibitor of graft versus host disease and can markedly inhibit the growth of cells from patients with the chronic-smoldering form of adult T cell leukemia.
- His group also has identified and characterized genome wide IL-2/STAT5 and IL-21/STAT3-based super-enhancers and studied chromatin interactions and the functional role of the super-enhancer in the gene encoding IL-2Rα, the gene he had cloned early in his career.
Dr. Warren J. Leonard received his A.B. in mathematics, magna cum laude and Phi Beta Kappa, from Princeton University and his M.D. from Stanford University. After completing residency training in medicine at Barnes Hospital and a year of research in biochemistry at Washington University in St. Louis, Dr. Leonard came to the NIH as a postdoctoral fellow in the Metabolism Branch, National Cancer Institute. He began directing his own laboratory in the Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development and then joined the NHLBI. Dr. Leonard is the recipient of many honors and awards, including the American Federation for Clinical Research Foundation Outstanding Investigator Award, the Food and Drug Administration Center for Biologics Evaluation and Research Outstanding Service Award, the American Association of Immunologists (AAI)-Huang Foundation Meritorious Career Award, and the Honorary Lifetime Membership Award of the International Cytokine and Interferon Society. Dr. Leonard has authored or coauthored more than 375 research and review articles and book chapters and holds 23 patents. He is currently an Associate Editor and former Co-Editor of Immunity, on the editorial board of Cytokine, an Associate Editor of International Immunology, and a contributing member of the Faculty of 1000. Moreover, he is past-President of the International Cytokine Society, a former member of the Board and former Vice President of the Foundation for Advanced Education in the Sciences (FAES), and has served on the Council of the Association of American Physicians. He is a member of the American Association of Immunologists, the American Society for Clinical Investigation, the Association of American Physicians, a Fellow of the American Association for the Advancement of Science, and a member of the National Academy of Inventors, the National Academy of Medicine, the National Academy of Sciences, and the American Academy of Arts and Sciences.
Dr. Leonard will accept the Milstein Award at Cytokines 2020 at the Awards Ceremony on Sunday, 1 November, 2020 at the Hyatt Regency Seattle and give a talk in the Opening Session.