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Warren J. Leonard, M.D.

Laboratory of Molecular Immunology

Scientific Focus Area(s): Clinical Research, Computational Biology, Genetics and Genomics, Molecular Biology and Biochemistry

Background

Warren Leonard received his A.B. in mathematics, magna cum laude and Phi Beta Kappa, from Princeton University in 1973 and his M.D. from Stanford University in 1977. After completing residency training in medicine at Barnes Hospital and a year of research in biochemistry at Washington University, Dr. Leonard came to the NIH as a postdoctoral fellow in the Metabolism Branch, National Cancer Institute in 1981. He began directing his own laboratory in the Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development in 1985 and then joined the NHLBI in 1992. Dr. Leonard is the recipient of many honors and awards, including the American Federation for Clinical Research Foundation Outstanding Investigator Award, Food and Drug Administration Center for Biologics Evaluation and Research Outstanding Service Award, and American Association of Immunologists (AAI)-Huang Foundation Meritorious Career Award. Dr. Leonard has authored or coauthored more than 300 articles and book chapters and holds 19 patents. He is currently on the editorial board of Cytokine and is an Associate Editor of International Immunology, an Associate Editor and former Co-Editor of Immunity, and a contributing member of the Faculty of 1000. Additionally, he is a Fellow of the American Association for the Advancement of Science and member of the American Society for Clinical Investigation and the Association of American Physicians. He is a Past-President of the International Cytokine Society, a member of the American Association of Immunologists, American Association for the Advancement of Science, and a member of the Board and former Vice President of the Foundation for Advanced Education in the Sciences.

Research Interests

Critical to proper development and orchestration of the cells that comprise the immune system are a number of intercellular signaling molecules, collectively known as cytokines, which act through multimeric receptors. Dr. Leonard’s laboratory focuses on the biology, signaling, and molecular regulation of a key family of these cytokines, the interleukins, with studies ranging from basic molecular mechanisms to human disease.

Early in his career, Dr. Leonard cloned and characterized the human receptor for the immune cytokine IL‑2, making him the first to clone the receptor for a type 1 cytokine. This led to studies in which he discovered the existence of the IL-2 receptor β chain and then to a major breakthrough in which he discovered that mutations in the gene encoding the human IL-2 receptor g chain result in X-linked severe combined immunodeficiency (XSCID, commonly known as the “Bubble Boy Disease”). Comparing the cellular phenotype of XSCID patients, who lack T cells and natural killer (NK) cells, with the known functions of IL-2, which does not affect T-cell or NK-cell development, Dr. Leonard predicted that the γ chain of the IL-2 receptor served a broader purpose, leading to his discovery that the γ chain is a common γ chain γ_c, that is shared by the receptor complexes for IL-4, IL-7, and IL-9; subsequent studies added IL-15 and IL-21 as γ_c family cytokines.

His 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 the study of primary human cells as well as mouse models. His laboratory has discovered multiple specific forms of immunodeficiency, including those caused by mutations in the genes encoding the intracellular signaling molecule JAK3, which associates with γ_c, and the receptor for IL-7.

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

Because of his expertise on γ_c, Dr. Leonard was involved in the first publication to report the TSLP receptor, a protein that is structurally related to the erythropoietin receptor but associates with the IL-7 receptor α 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 γ_c family cytokines, combining state-of-the-art methodologies such as ChIP-Seq, RNA-Seq, 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. Moreover, his lab also uses next generation sequencing to search for the causes of select types of immune-related diseases, including unidentified immunodeficiencies.

Selected Publications

BATF-JUN is critical for IRF4-mediated transcription in T cells.
Li P, Spolski R, Liao W, Wang L, Murphy TL, Murphy KM, Leonard WJ.
Nature. 2012 Oct 25;490:543-6.
[Text Abstract on PubMed]

Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function.
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.
Immunity. 2012 Apr 20;36:586-99.
[Text Abstract on PubMed]

Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages.
Liao W, Lin JX, Wang L, Li P, Leonard WJ.
Nat. Immunol.. 2011 Jun;12:551-9.
[Text Abstract on PubMed]

A critical role for IL-21 in regulating immunoglobulin production.
Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, Morse, Liu C, Schwartzberg PL, Leonard WJ.
Science. 2002 Nov 22;298:1630-4.
[Text Abstract on PubMed]

Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans.
Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ.
Cell. 1993 Apr 9;73:147-57.
[Text Abstract on PubMed]

Warren J. Leonard's Full List of Publications