Molecular Immunology

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 (IL-2Ralpha), the first cloning of a receptor for a type 1 cytokine. He then discovered the existence of the IL-2 receptor beta chain (IL-2Rbeta) and then had a major breakthrough in which he discovered that mutations in the gene (IL2RG) encoding the human IL-2 receptor gamma chain (IL-2Rgamma) 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-2Rgamma serves a broader purpose and demonstrated that it is a common gamma chain, shared by the receptor complexes for IL-4, IL-7, and IL-9. Subsequent studies added IL-15 and IL-21 as additional common gamma chain 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 JAK3-deficient SCID and IL7R-deficient SCID. JAK3 encodes a signaling molecule, JAK3, which associates with the common gamma chain, whereas IL7R encodes the receptor for IL-7. Finding that JAK3 mutations result in immunodeficiency led Dr. Leonard and colleagues to hypothesize that inhibitors of JAK3 would be immunosuppressive, with the development of tofacitinib by Pfizer (FDA-approved in 2012); a broad range of other JAK inhibitors are now in clinical use, demonstrating the broad utility of this class of therapeutics. In addition, Il2rg-deficient mice, as developed by the lab, were used in the generation of widely used NOG and NSG mice.

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 also 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 (TSLPR), a protein that associates with IL-7Ralpha to transduce TSLP signaling. In a mouse model of asthma, Dr. Leonard showed that TSLP is vital to the development of allergic lung inflammation and made other major discoveries related to TSLP.

Dr. Leonard currently engages in a range of studies of common gamma chain family cytokines, TSLP, 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, neokines, and new regulatory molecules and processes, as well as to translational/therapeutic advances.