IL-2 Family Cytokines and their Receptors-- Biology of the IL-21 system

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The IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, we discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans. We reported in 1995 that mutations of the gc-associated kinase, JAK3, result in an autosomal recessive form of SCID indistinguishable from XSCID and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on work in our lab and others, gc was previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Related to IL-21, we previously cloned the IL-21 receptor, generated IL-21 transgenic mice and IL-21R knockout mice, elucidated the mechanism of IL-21 signaling, showed that IL-21 drives the differentiation of Th17 cells (which are important in pathological processes such as Crohn's disease), and critically regulates immunoglobulin production. A range of data also implicated IL-21 as serving a possible role in autoimmunity, particularly in lupus, with elevated IL-21 levels in the BXSB-Yaa mouse model of lupus. Moreover, prior studies from the lab indicated the possible utility of IL-21 as an anti-tumor agent. We previously showed that IL-21 plays a critical role in autoimmune diabetes, and during 2009, in a collaboration with Derry Roopenian at the Jackson Lab, we demonstrated that IL-21 signaling is essential for the development of systemic lupus erythematosus in the BXSB-Yaa mouse model of SLE. We also analyzed the role of IL-21 related to the development of T follicular helper cells and Th17 cells and generated data in a collaborative study that IL-21 is anti-tolerogenic cytokine in the late-phase alloimmune response. In collaborative studies, we showed that IL-21 is critical for graft versus host disease (GVHD) in a mouse model. These data suggest that IL-21 is an important regulator of GVHD and that blocking IL-21 could represent a novel therapeutic strategy for attenuating or preventing this problem associated with transplantation. Moreover, we demonstrated that IL-21 promotes GVHD through enhanced production of effector CD4 T cells. Interestingly, we also showed that GVL and graft versus host disease (GVHD) are immunologically distinguishable events based on IL-21 signaling. Moreover, the lack of an IL-21 signal attenuates graft versus leukemia (GVL) in the absence of CD8 T cells. Extending earlier studies on the role of IL-21 in B cell biology, IL-21R was shown to be functional as early as pro-B cells and the addition of IL-21 to B cell progenitors resulted in the appearance of B cell maturation markers. The data collectively supported an early role for IL-21 in regulating B cell development. It was also revealed that IL-21 signaling is required for CD8 T cell survival and memory cell formation in response to vaccinia viral infection and that IL-21 was pivotal in determining age-dependent immune responses in a mouse model of hepatitis, a finding with broad implications in potentially explaining why decreased production of IL-21 in younger patients may prevent critical CD8 T and B cell responses, with viral clearance in most adults and chronic HBV in neonates and children. Finally, we demonstrated that IL-21 is critical for the development of experimental autoimmune uveitis in a mouse model of a similar human disease and showed markedly defective adoptive transfer of disease by IL-21R-deficient T cells. We in fact generated IL-2-emerald GFP/IL-21-mCherry dual reporter mice, and found IL-2/IL-21 double producing cells in the retina. Overall, our studies help to improve our understanding of signaling by the gc family cytokine IL-21. Our findings clarify molecular mechanisms that are relevant to autoimmunity, and cancer, as well as to the basic control of T-cell and B-cell actions.