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 γ 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 γc, that is shared by the receptor complexes for IL-4, IL-7, and IL-9; subsequent studies added IL-15 and IL-21 as γc 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 γc, 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 γc, 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 γc family cytokines, STAT proteins, and regulatory processes, combining state-of-the-art methodologies such as ChIP-Seq, RNA-Seq, ATAC-Seq, ChIA-PET, 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.