IL-2 and related cytokine 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 differentiation of Th17 cells (which mediate pathological processes such as Crohn's disease), and critically regulates immunoglobulin production. We and others implicated IL-21 as serving a key role in autoimmune disease, including lupus and type 1 diabetes, and indicated the possible utility of IL-21 as an anti-tumor agent. 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 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 that helps to explain 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 previously also found that IL-21 promotes the pathogenic response to pneumonia virus of mice (PVM), which is highly related to human respiratory syncytial virus. Interestingly, after infection of Il21r-deficient mice with PVM, there was less infiltration of neutrophils and fewer CD8, CD4, and gamma-delta T cell numbers in the lungs. 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. Finally, with Tom Tedder, we previously showed that IL-21 could expand B regulatory cells that produce IL-10 (B10 cells). In the current year, we continued our studies on the biological actions of IL-21. 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 prior discovery that in contrast to its 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 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. In the current year, we have continued our studies of AICEs and the importance of the IRF4/BATF/JUN/STAT3 complex. IL-21 has broad actions on T- and B-cells, but its actions in innate immunity are poorly understood. Previously, 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). We have continued our studies of the role of IL-21 in DC biology. 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.