Warren J. Leonard

Established the mechanisms underlying the function of key immune system cytokines and their roles in human disease. Cloned the IL-2 receptor alpha-chain and discovered IL-2Rbeta, thus delineating the first type I cytokine receptor. Demonstrated the existence of a family of related cytokines that all use a receptor containing the common gamma-chain , including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, and showed that mutations in common gamma resulted in human X-linked severe combined immunodeficiency (X-SCID). He demonstrated that the kinase JAK3 associates with common gamma and discovered that JAK3 mutations result in autosomal-recessive SCID that phenocopies X-SCID. He also showed that mutations in the IL-7Ralpha chain cause T-B+NK+ SCID, revealing that IL-7 is critical for human T-cell development. Leonard cloned the IL-21 receptor and demonstrated that the intrinsic B-cell defect in X-SCID results from simultaneous inactivation of signaling by IL-4 and IL-21 and that IL-21 drives plasma-cell differentiation, and broadly elucidated the biology, signaling and gene activation events mediated by IL-21. He further demonstrated the role of an IL-7-like cytokine, TSLP, in an inflammation model of asthma. Collectively, his work has shown a central role for common gamma-family cytokines in the development of the adaptive immune system and in mechanisms underlying immunodeficiency and leukemia.