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 IL-21 drives the differentiation of Th17 cells (which mediate 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, our prior studies 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 (Jackson Lab), we showed 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. We also previously showed that IL-21 is critical for graft versus host disease (GVHD) in a mouse model, and thus 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. We also previously found 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. We also had 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 reportermice, and found IL-2/IL-21 double producing cells in the retina. In the previous year, we reported that IL-21 can promote the pathogenic response to pneumonia virus of mice (PVM), or pneumovirus, which is highly related to human respiratory syncytial virus. PVM-infected mice expressed IL-21 in CD4+ T cells. Interestingly, after infection Il21r-deficient mice had lessinfiltration of neutrophils, as well as fewer CD8, CD4, and gamma-delta T cell numbers in the lungs. Strikingly, Il21r-deficient mice exhibited enhanced survival, and treatment of wild type mice with an IL-2R-Fc fusion protein enhanced the survival of these animals. These data indicated that IL-21 plays an important role in mediating the inflammatory response to PVM and suggest that inhibiting the action of PVM could represent a mechanism for treatment PVM and potentially other viral infections. Previously, we demonstrated that IL-21 regulated expression of the Prdm1 gene that encodes BLIMP1 via a response element that depends on STAT3 and IRF4. This led to our discovering in the past year that in contrast to its known ability to cooperate with PU.1 in B cells to act via Ets-IRF composite elements (EICEs), IRF4 cooperates with BATF/JUN family proteins to act via AP1-IRF composite elements (AICEs) in T cells, as well as in B cells. We demonstrated critical cooperative regulation of important genes via these AICEs and demonstrated cooperative binding of IRF4, BATF, and JUN family proteins, with markedly diminished IRF4 binding in Batf-deficient cells and markedly diminished BATF binding in Irf4-deficient cells. We demonstrated critical regulation of key genes, including for example those encoding IL-10 and IL-17 via AICEs. In collaborative studies with Ken Murphy, we also demonstrated important compensatory roles for BATF factors in dendritic cell development mediated by BATF-IRF interactions involving the leucine zipper domain of BATF. In a collaborative study with Tom Tedder, we reported the role of IL-21 in the expansion regulatory B cells, which produce IL-10 (B10 cells). Corresponding to earlier findings that IL-21 potently induces expression of IL-10, it was shown that regulatory B cells control T cell autoimmune disease via IL-21 and CD40 dependent cognate interactions and that ex vivo signaling via IL-21 and CD40 allowed dramatic expansion of effector B10 cells that could markedly decrease disease symptoms in animals with established experimental autoimmune encephalitis. In another study with Dr. Tedder, it was reported that B10 cell expansion during Listeria infection governs innate and cellular immune responses in mice. IL-21 has broad actions on T- and B-cells, but its actions in innate immunity are poorly understood. In the past year, we reported that IL-21 induces apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive alpha c-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive-transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon (IFN)-γ-producing CD4+ T cells in Il21r-/-Rag2-/- mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2-/- mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response. In other collaborative studies, we demonstrated with Manfred Kopf that IL-21 restricts virus driven Treg expansion in chronic LCMV infection, with Rafi Ahmed that IL-21 is critical for the generation of long-lived plasmid cells, and with Richard Flavell that eExcessive Th1 responses due to the absence of TGF-mediated signaling cause autoimmune diabetes and dysregulated Treg cell homeostasis. Overall, our studies have elucidated the biology and mechanism of action by the gc family cytokine IL-21. Our findings are relevant to autoimmunity and cancer, as well as to the basic control of T-cell and B-cell actions.

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Naradikian, Martin S; Myles, Arpita; Beiting, Daniel P et al. (2016) Cutting Edge: IL-4, IL-21, and IFN-γ Interact To Govern T-bet and CD11c Expression in TLR-Activated B Cells. J Immunol 197:1023-8
Sakuraba, Koji; Oyamada, Akiko; Fujimura, Kenjiro et al. (2016) Interleukin-21 signaling in B cells, but not in T cells, is indispensable for the development of collagen-induced arthritis in mice. Arthritis Res Ther 18:188
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