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

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IL-2 and related cytokine systems are studied to clarify the immune response in normal, neoplastic, immunodeficient, and other disease states. Following activation by antigen, the magnitude and duration of the T-cell immune response is determined by the 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, the lab co-discovered IL-2Rb in 1986 and then 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 autosomal recessive SCID that phenocopies XSCID and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on our work 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. We previously cloned IL-21R, generated IL-21 transgenic and Il21r knockout mice, elucidated mechanisms of IL-21 signaling, showed with Dan Littman that IL-21 promotes Th17 differentiation, and regulate immunoglobulin production. We showed IL-21 serves key roles in autoimmune disease, including in mouse models of lupus, type 1 diabetes, and uveitis, and indicated potential for IL-21 as an anti-tumor agent. We showed a role for IL-21 in the development of T follicular helper cells and that IL-21 signaling is required for CD8 T cell survival and memory cell formation. We previously found that IL-21 promotes the pathogenic response to pneumonia virus of mice and that IL-21 induces IL-10 and with Tom Tedder that IL-21 could expand regulatory B cells (Breg cells) that produce IL-10 (B10 cells). Previously, we demonstrated that IL-21 regulated the Prdm1 gene (encoding BLIMP1) via STAT3 and IRF4, leading to our finding that unlike its ability to cooperate with PU.1 in B cells via ETS-IRF composite elements (EICEs), IRF4 cooperates with BATF/JUN family proteins to act via AP1-IRF composite elements (AICEs) in T cells and some B cells. IL-21 broadly acts on T- and B-cells, but its actions in innate immunity are poorly understood. Previously, we also showed IL-21 induces apoptosis of conventional dendritic cells (cDCs) via STAT3 and BIM, and this was inhibited by GM-CSF. We also previously showed that IL-21 induces IL-1 production in cDCs via a STAT3-dependent but NF-kB-independent pathway. STAT3-dependent IL-1 expression in cDCs partially explains the IL-21-mediated pathologic response occurring during infection with PVM. We also previously showed that IL-1 receptor signaling is critical for the development of autoimmune uveitis, a process we showed was dependent on IL-21. Mechanistically, IL-21 activates several STAT proteins. Besides signaling via STAT3, STAT1 is also important, and we had found that Tbx21 (encoding Tbet) and Ifng are differentially regulated by these STATs, with opposing actions of STAT1 and STAT3 on IFN- expression in CD4(+) T cells during chronic LCMV infection, and moreover, concordant actions of IL-21 related to IFNG and TBX21 expression was found using CD4 T cells from patients with hyper-IgE syndrome, a disease caused by STAT3 mutations, as well as in cells from STAT1 gain-of-function patients. Thus, STAT1 vs. STAT3 activation can fine-tune the actions of IL-21. We also previously found opposing roles for IL-21 and IL-2 in Th9 differentiation and contributed to studies showing that IL-21 with IFNg and IL-4 can govern TBET and CD11c expression in TLR-activated B cells, and that IL-21 signaling in B cells but not T cells is essential for the development of collagen-induced arthritis in mice. We previously reported an interplay between IL-21 and type I IFN that regulates neutrophil-dependent responses to S. aureus and showed IL-2 and IL-21 differentially influence CD8+ T cell differentiation. Moreover, we had shown that IL-2 drives terminal differentiation to cells poorly effective against tumors, but IL-21 promotes stem cell memory T cells (TSCM) and antitumor responses. IL-2 promoted effector-like metabolism and aerobic glycolysis, inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a more quiescent state. LDH inhibition rewired IL-2-induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of NR4A family nuclear receptors, as well as Prdm1 and Xbp1. Deleting Ldha prevented development of cells with antitumor effector function, but transient LDH inhibition increased memory cells that exhibited antitumor efficacy after adoptive transfer. Moreover, combining LDH inhibition with IL-21 increased TSCM cells, with greater antitumor responses and host survival, showing LDH modulates cytokine-mediated T cell differentiation, with translational potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy. We previously also investigated the effect of cytokines on the cytolytic activity of exosomes derived from NK cells. Extracellular vesicles (EVs) derived from NK cells (NK-EVs), including exosomes, possess cytotoxic capacity against tumor cells, but their characteristics and regulation by cytokines had not been studied. We found that EVs from human NK-92 cells stimulated with IL-15 + IL-21 had enhanced cytotoxic capacity, that granzymes B and H were induced by IL-15 + IL-21 stimulation in NK-EVs but were not required for the cytotoxic capacity. Thus, we elucidated novel properties of NK-EVs. We also contributed to a study showing that proliferation, together with increased apoptosis, causes T-cell lymphopenia in endogenous Cushings patients. IL-21 was decreased in high-dose glucocorticoid environments, and adding IL-21 reversed glucocorticoid therapy-induced apoptosis. Thus, administering IL-21 in patients receiving long-term, high-dose glucocorticoid therapy might be beneficial. We previously collaborated with Brian Annex to show that the loss of IL-21 receptor activation in hypoxic endothelial cells impaired perfusion recovery after hindlimb ischemia and showed there is increased endothelial IL-21 receptor expression in peripheral artery disease and furthermore with him reported that microRNA-30b is necessary and sufficient for IL-21-mediated angiogenesis in peripheral arterial disease. In the past year, we have generated exciting work on IL-21 neokines/mimetics with David Baker, worked on the role of IL-21 in other cell types and investigated mechanisms of IL-21-induced signaling and aspects of IL-21 biology. Overall, our studies have elucidated the biology/mechanisms of IL-21, expanding our knowledge of normal and pathological immune cell function, with relevance to autoimmunity and cancer, as well as to the basic control of T-cell and B-cell actions, with potential therapeutic implications.