Warren Leonard, M.D.

NIH Distinguished Investigator

Molecular Immunology


10 Center Dr
BG 10 RM 7B05
Bethesda, MD 20814
United States



Research Topics

Cytokines are critical secreted molecules that control the development, growth, differentiation, and function of cells that comprise the immune system. Dr. Leonard’s laboratory focuses on the biology, signaling, and molecular regulation of a key family of these cytokines, the common gamma chain family of cytokines, with studies ranging from basic molecular mechanisms to human disease.

Early in his career, Dr. Leonard characterized the human receptor for the immune cytokine IL‑2, and cloned the IL-2 receptor alpha chain, the first cloning of a receptor for a type 1 cytokine. He then discovered the existence of the IL-2 receptor beta chain and then had a major breakthrough and discovered that mutations in the gene encoding the human IL-2 receptor gamma chain result in X-linked severe combined immunodeficiency (XSCID, also known as the “Bubble Boy Disease”) in humans. Because XSCID patients lack T cells and natural killer (NK) cells, whereas IL-2 deficiency does not affect T-cell or NK-cell development, Dr. Leonard predicted that IL-2R gamma serves a broader purpose and demonstrated that the gamma chain is a common gamma chain gamma c, shared by the receptor complexes for IL-4, IL-7, and IL-9; subsequent studies added IL-15 and IL-21 as gamma c family cytokines.

Dr. Leonard’s laboratory applies a broad range of methodologies to both human cells and mouse models and relies on the continual interplay between basic research, which teases apart the signaling mechanisms that underlie normal immune cell development, and clinical/mouse phenotypes. His laboratory has discovered multiple specific forms of immunodeficiency, including those caused by mutations in the genes encoding the intracellular signaling molecule JAK3-deficient SCID, which associates with gamma c, and the receptor for IL-7.

Dr. Leonard’s lab also cloned the receptor for IL-21, a pleiotropic cytokine with broad actions, including in T and B cell biology and has elucidated its roles as an anti-cancer agent as well as a cytokine that promotes autoimmune disease. In animal models, the lab demonstrated key roles for IL-21 in the development of type 1 diabetes, lupus, and experimental allergic uveitis.

The lab also contributed to the first publication to report the cloning of the TSLP receptor, a protein that associates with the IL-7 receptor alpha chain to transduce TSLP signaling. In a mouse model of asthma, Dr. Leonard has shown that TSLP is vital to the development of allergic lung inflammation.

Dr. Leonard currently engages in a range of studies of gamma c family cytokines, STAT proteins, and regulatory processes, combining state-of-the-art methodologies such as ChIP-Seq, RNA-Seq, ATAC-Seq, ChIA-PET, Hi-ChIP, and other molecular techniques with the analysis of human cells as well as transgenic, knock-in, and knockout mouse models to elucidate the biology and mechanisms involved in important in vivo processes. Current projects relate to super-enhancers and their regulation via epigenetics and transcription factors, cytokine partial agonists, and new regulatory molecules and processes, as well as to translational/therapeutic advances.


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, the Honorary Lifetime Membership Award of the International Cytokine and Interferon Society, the Milstein Award of the International Cytokine and Interferon Society, and the Harrington Prize. Dr. Leonard has authored or coauthored more than 400 articles and book chapters and holds 25 patents. He is currently an Advisory Board member and former Co-Editor of Immunity and on the Editorial Board of the Proceedings of the National Academy of Sciences. Moreover, he is Past-president of the International Cytokine Society, former Vice President of the Foundation for Advanced Education in the Sciences (FAES) and former member of the Council of the Association of American Physicians, a member of the National Academy of Inventors, 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, a member of the Henry Kunkel Society, and a member of the National Academy of Medicine (formerly the Institute of Medicine), the National Academy of Sciences, and the American Academy of Arts and Sciences.

Selected Publications

  1. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993;73(1):147-57.
  2. Lin JX, Li P, Liu D, Jin HT, He J, Ata Ur Rasheed M, Rochman Y, Wang L, Cui K, Liu C, Kelsall BL, Ahmed R, Leonard WJ. Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function. Immunity. 2012;36(4):586-99.
  3. Li P, Spolski R, Liao W, Wang L, Murphy TL, Murphy KM, Leonard WJ. BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature. 2012;490(7421):543-6.
  4. Mitra S, Ring AM, Amarnath S, Spangler JB, Li P, Ju W, Fischer S, Oh J, Spolski R, Weiskopf K, Kohrt H, Foley JE, Rajagopalan S, Long EO, Fowler DH, Waldmann TA, Garcia KC, Leonard WJ. Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps. Immunity. 2015;42(5):826-38.
  5. Li P, Mitra S, Spolski R, Oh J, Liao W, Tang Z, Mo F, Li X, West EE, Gromer D, Lin JX, Liu C, Ruan Y, Leonard WJ. STAT5-mediated chromatin interactions in superenhancers activate IL-2 highly inducible genes: Functional dissection of the Il2ra gene locus. Proc Natl Acad Sci U S A. 2017;114(46):12111-12119.

Related Scientific Focus Areas

This page was last updated on Tuesday, April 23, 2024