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		Search Text: Home/< Back ToThe Science/Molecular Immunology
  Molecular Immunology
    Cytokines are critical secreted molecules that control the development, growth, differentiation, and function of cells that comprise the immune system. The Laboratory of Molecular Immunology, led by Dr. Warren J. Leonard, 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.
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          Warren Leonard
  Warren Leonard, M.D.
          NIH Distinguished Investigator
          Email
      Meet the Team
            Contact us
  Senior Investigator Research Interests
            
  Research Interests
              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.
  Featured Publications
                Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans.
            Authors:Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ
                                                                                                                        
            Cell
      
                1993 Apr 09;73(1):147-57
        Read Publication
                      Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps.
            Authors: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
                                                                                                                        
            Immunity
      
                2015 May 19;42(5):826-38
        Read Publication
                      LDH inhibition and IL-21 synergize to promote CD8+ T cell stemness and antitumor immunity
            Authors:D. Hermans, S. Gautam, J.C. García-Cañaveras, D. Gromer, S. Mitra, R. Spolski, P. Li, S. Christensen, R. Nguyen, J.-X. Lin, J. Oh, N. Du, S. Veenbergen, J. Fioravanti, R. Ebina-Shibuya, C. Bleck, L.M. Neckers, J.D. Rabinowitz, L. Gattinoni, W.J. Leonard
                                                                                            
            Proc. Natl. Acad. Sci. USA;117:6047-6055
        Read Publication
                      An engineered IL-2 partial agonist promotes CD8+ T cell stemness
            Authors:F. Mo, Z. Yu, P. Li, J. Oh, R. Spolski, L. Zhao, C.R. Glassman, T.N. Yamamoto, Y. Chen, F.M. Golebiowski, D. Hermans, S. Majri-Morrison, L.K. Picton, W. Liao, M. Ren, X. Zhuang, S. Mitra, J.-X. Lin, L. Gattinoni, J.D. Powell, N.P. Restifo, K.C. Garcia
                                                                                                                        
            Nature
      
                2021 Sep 01;597(7877):544-548
        Read Publication
                      Distinct utilization of super-enhancer elements controls CD25 transcription and function in a cell-type specific fashion
            Authors:Spolski R, Li P, Chandra V, Shin B, Goel S, Liu C, Oh J, Ren M, Enomoto Y, West EE, Christensen S, Wan ECK, Ge M, Lin JX, Yan B, Kazemian M, Yu ZX, Nagao K, Vijayanand P, Rothenberg EV, Leonard WJ
                                                                                                                        
            Science Immunology
      
                2023 Nov 03;8(89):
        Read Publication
  Meet the Team

    Warren Leonard

            Warren Leonard, M.D.
                NIH Distinguished Investigator
                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.
    
          Contact the lab
    10 Center DrBethesda, MD 20814United States
        Phone:
                    301-496-0098
                Fax:
            301-402-0971
  Md Masud Alam, Ph.D.
        

    Research Fellow

        md.alam@nih.gov
            Dr. Sonali Das
    
            Sonali Das, Ph.D.
        

    Visiting Fellow

        sonali.das@nih.gov
            Tesfay Gebregiorgis
    
            Tesfay Gebregiorgis
        

    Scientific Support Staff

        gebregiorgist@mail.nih.gov
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            Spencer Gill, Ph.D.
        

    Post-doctoral Fellow

        spencer.gill@nih.gov
            Wei Liao
    
            Wei Liao, M.D., Ph.D.
        

    Biologist

        liaow@mail.nih.gov
            Jian Xin Lin
    
            Jian Xin Lin, M.D., Ph.D.
        

    Staff Scientist

        linjx@nhlbi.nih.gov
            Jyothi Padiadpu, Ph.D.
        

    Staff Scientist

        jyothi.padiadpu@nih.gov
            blank avatar
    
            Hrishikesh Pandit, Ph.D.
        

    Visiting Fellow

        hrishikesh.pandit@nih.gov
            Suyasha Roy, Ph.D.
    
            Suyasha Roy, Ph.D.
        

    Visiting Fellow

        suyasha.roy@nih.gov
            Rosanne Spolski
    
            Rosanne Spolski, Ph.D.
        

    Staff Scientist

        spolskir@nhlbi.nih.gov
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