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1.  The Cytokines IL-21 and GM-CSF have Opposing Regulatory Roles in the Apoptosis of Conventional Dendritic Cells 
Immunity  2013;38(3):514-527.
Interleukin-21 (IL-21) has broad actions on T- and B-cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced 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 α-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.
doi:10.1016/j.immuni.2013.02.011
PMCID: PMC3705920  PMID: 23453633
IL-21; GM-CSF; apoptosis; dendritic cells
2.  Regulatory B Cell (B10 Cell) Expansion During Listeria Infection Governs Innate and Cellular Immune Responses In Mice 
Pathogens use numerous methods to subvert host immune responses, including the modulation of host IL-10 production by diverse cell types. However, the B cell sources of IL-10 and their overall influence on innate and cellular immune responses have not been well characterized during infections. Using Listeria as a model pathogen, infection drove the acute expansion of a small subset of regulatory B cells (B10 cells) that potently suppress inflammation and autoimmunity through the production of IL-10. Unexpectedly, spleen bacteria loads were 92–97% lower in B10 cell-deficient CD19−/− mice, in mice depleted of mature B cells, and in mice treated with CD22 mAb to preferentially deplete B10 cells before infection. By contrast, the adoptive transfer of wild type B10 cells reduced bacterial clearance by 38-fold in CD19−/− mice through IL-10-dependent pathways. B10 cell depletion using CD22 mAb significantly enhanced macrophage phagocytosis of Listeria and their production of IFN-γ, TNF-α, and nitric oxide ex vivo. Accelerated bacteria clearance following B10 cell depletion significantly reduced Ag-specific CD4+ T cell proliferation and cytokine production, but did not alter CD8+ T cell responses. B10 cell regulatory function during innate immune responses was nonetheless dependent on cognate interactions with CD4+ T cells since B10 cells deficient in IL-10, MHC-II or IL-21 receptor expression did not influence Listeria clearance. Thus, Listeria manipulates immune responses through a strategy of immune evasion that involves the preferential expansion of endogenous B10 cells that regulate the magnitude and duration of both innate and cellular immune responses.
doi:10.4049/jimmunol.1201427
PMCID: PMC3552111  PMID: 23275601
B cells; Listeria monocytogenes; innate immunity; regulatory B cells; B10 cells
3.  Interleukin-21 Is a Critical Cytokine for the Generation of Virus-Specific Long-Lived Plasma Cells 
Journal of Virology  2013;87(13):7737-7746.
Long-lived plasma cells that reside in the bone marrow constitutively produce antibody in the absence of antigen and are the cellular basis of durable humoral immunity. The generation of these long-lived plasma cells depends upon a series of highly orchestrated interactions between antigen-specific CD4 T cells and B cells and the formation of germinal centers (GCs). In this study, we have examined the role of the cytokine interleukin-21 (IL-21) in regulating humoral immunity during acute viral infections. Using IL-21 receptor-deficient (IL-21R−/−) mice, we found that virus-specific CD4 T cells were generated after infection with lymphocytic choriomeningitis virus (LCMV) and that these CD4 T cells differentiated into T follicular helper (TFH)-like cells in the absence of IL-21 signaling. There was also no defect in the formation of GCs, although after day 15 these GCs disappeared faster in IL-21R−/− mice than in wild-type mice. Isotype switching and the initial LCMV-specific IgG response were normal in IL-21R−/− mice. However, these mice exhibited a profound defect in generating long-lived plasma cells and in sustaining antibody levels over time. Similar results were seen after infection of IL-21R−/− mice with vesicular stomatitis virus and influenza virus. Using chimeric mice containing wild-type or IL-21R−/− CD4 T cells and B cells, we showed that both B and CD4 T cells need IL-21 signaling for generating long-term humoral immunity. Taken together, our results highlight the importance of IL-21 in humoral immunity to viruses.
doi:10.1128/JVI.00063-13
PMCID: PMC3700268  PMID: 23637417
4.  Cd14 SNPs Regulate the Innate Immune Response 
Molecular Immunology  2012;51(2):112-127.
CD14 is a monocytic differentiation antigen that regulates innate immune responses to pathogens. Here, we show that murine Cd14 SNPs regulate the length of Cd14 mRNA and CD14 protein translation efficiency, and consequently the basal level of soluble CD14 (sCD14) and type I IFN production by murine macrophages. This has substantial downstream consequences for the innate immune response; the level of expression of at least 40 IFN-responsive murine genes was altered by this mechanism. We also observed that there was substantial variation in the length of human CD14 mRNAs and in their translation efficiency. sCD14 increased cytokine production by human dendritic cells (DCs), and sCD14-primed DCs augmented human CD4 T cell proliferation. These findings may provide a mechanism for exploring the complex relationship between CD14 SNPs, serum sCD14 levels, and susceptibility to human infectious and allergic diseases.
doi:10.1016/j.molimm.2012.02.112
PMCID: PMC3341513  PMID: 22445606
5.  Mechanistic and structural insight into the functional dichotomy between interleukin-2 and interleukin-15 
Nature immunology  2012;13(12):1187-1195.
Interleukin-15 (IL-15) and IL-2 possess distinct immunological functions despite both signaling through IL-2Rβ and the common cytokine receptor γ-chain, γc, We find that in the IL-15—IL-15Rα—IL-2Rβ—γc quaternary complex structure, IL-15 heterodimerizes IL-2Rβ and γc identically to the IL-2—IL-2Rα—IL-2Rβ—γc complex, despite differing receptor-binding chemistries. IL-15Rα dramatically increases the affinity of IL-15 for IL-2Rβ, and this allostery is required for IL-15 trans-signaling versus IL-2 cis-signaling. Consistent with the identical IL-2Rβ—γc dimer geometry, IL-2 and IL-15 exhibited similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induce similar signals, and the cytokine-specificity of IL-2Rα versus IL-15Rα determines cellular responsiveness. These results provide important new insights for specific development of IL-15-versus IL-2-based immunotherapeutics.
doi:10.1038/ni.2449
PMCID: PMC3501574  PMID: 23104097
6.  BATF-JUN is critical for IRF4-mediated transcription in T cells 
Nature  2012;490(7421):543-546.
Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response1,2. IRF4 binds DNA weakly due to a C-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity3, allowing IRF4 to regulate genes containing ETS/IRF composite elements (EICEs; 5′-GGAAnnGAAA-3′)1. Here, we show that in CD4+ T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with Activator Protein-1 (AP-1) complexes to bind to AP-1/IRF4 composite (TGAnTCA/GAAA) motifs that we denote as AP-1/IRF composite elements (AICEs). Moreover, BATF/Jun family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4+ T cells stimulated with IL-21 and in Th17 differentiated cells. Importantly, BATF binding was diminished in Irf4−/− T cells and IRF4 binding was diminished in Batf−/− T cells, consistent with functional cooperation between these factors. Moreover, we show that AP-1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in Th17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP-1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription.
doi:10.1038/nature11530
PMCID: PMC3537508  PMID: 22992523
7.  IL-21 Promotes the Pathologic Immune Response to Pneumovirus Infection 
IL-21 is a cytokine with pleiotropic actions, promoting terminal differentiation of B cells, increased immunoglobulin production, and the development of Th17 and T follicular helper cells. IL-21 is also implicated in the development of autoimmune disease and has anti-tumor activity. Here we investigated the role of IL-21 in host-defense to pneumonia virus of mice (PVM), which initiates an infection in mice resembling that of respiratory syncytial virus disease in humans. We found that PVM-infected mice expressed IL-21 in lung CD4+ T cells. Following infection, Il21r-/- mice exhibited less lung infiltration by neutrophils than did WT mice and correspondingly had lower levels of the chemokine CXCL1 in bronchoalveolar lavage fluid and lung parenchyma. CD8+, CD4+, and γδ T-cell numbers were also lower in the lungs of PVM-infected Il21r-/- mice than in infected WT mice, with normal Th17 cytokines but diminished IL-6 production in PVM-infected Il21r-/- mice. Strikingly, Il21r-/- mice had enhanced survival following PVM-infection, and moreover, treatment of WT mice with soluble IL-21R-Fc fusion protein enhanced their survival. These data reveal that IL-21 promotes the pathogenic inflammatory effect of PVM and indicate that manipulating IL-21 signaling may represent an immunomodulatory strategy for controlling PVM and potentially other respiratory virus infections.
doi:10.4049/jimmunol.1100767
PMCID: PMC3277853  PMID: 22238461
8.  Thymic Stromal Lymphopoietin is Produced by Dendritic Cells1 
TSLP is a type 1 cytokine that contributes to lymphopoiesis and the development of asthma and atopic dermatitis. TSLP acts on multiple lineages, including dendritic cells (DCs), T cells, NKT cells, eosinophils, and mast cells, mediating proliferation and survival, and linking innate and adaptive immune responses. TSLP is produced by a range of cells, including epithelial cells, fibroblasts, stromal cells, and keratinocytes. DCs are important primary targets of TSLP, and we now unexpectedly demonstrate that DCs also produce TSLP in response to Toll-like receptor (TLR) stimulation and that this is augmented by IL-4. Moreover, we demonstrate that when mice are challenged with house dust-mite (HDM) extract, lung CD11c+ DCs express TSLP mRNA at an even higher level than epithelial cells. These data suggest that DCs not only respond to TSLP but also are a source of TSLP during pathogen and/or allergen encounter.
doi:10.4049/jimmunol.1100355
PMCID: PMC3140600  PMID: 21690322
9.  Spontaneous development of IL-17-producing γδ T cells in the thymus occurs via a TGFβ1-dependent mechanism1 
In naïve animals, γδ T cells are innate sources of IL-17, a potent proinflammatory cytokine mediating bacterial clearance as well as autoimmunity. However, mechanisms underlying the generation of these cells in vivo remain unclear. Here we show that TGFβ1 plays a key role in the generation of IL-17+ γδ T cells, and that it mainly occurs in the thymus particularly during the postnatal period. Interestingly, IL-17+ γδ TCR+ thymocytes were mainly CD44highCD25low cells, which seem to derive from DN4 γδ TCR+ cells that acquired CD44 and IL-17 expression. Our findings identify a novel developmental pathway during which IL-17-competent γδ T cells arise in the thymus by a TGFβ1-dependent mechanism.
doi:10.4049/jimmunol.0903539
PMCID: PMC2844788  PMID: 20061408
γδ T cells; IL-17; TGFβ
10.  IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B 
The Journal of Clinical Investigation  2011;121(3):1154-1162.
HBV is a noncytopathic hepadnavirus and major human pathogen that causes immune-mediated acute and chronic hepatitis. The immune response to HBV antigens is age dependent: viral clearance occurs in most adults, while neonates and children usually develop chronic infection and liver disease. Here, we characterize an animal model for HBV infection that recapitulates the key differences in viral clearance between early life and adulthood and find that IL-21 may be part of an effective primary hepatic immune response to HBV. In our model, adult mice showed higher HBV-dependent IL-21 production in liver, compared with that of young mice. Conversely, absence of the IL-21 receptor in adult mice resulted in antigen persistence akin to that of young mice. In humans, levels of IL-21 transcripts were greatly increased in blood samples from acutely infected adults who clear the virus. These observations suggest a different model for the dichotomous, age-dependent outcome of HBV infection in humans, in which decreased IL-21 production in younger patients may hinder generation of crucial CD8+ T and B cell responses. These findings carry implications for therapeutic augmentation of immune responses to HBV and potentially other persistent liver viruses.
doi:10.1172/JCI44198
PMCID: PMC3049376  PMID: 21393863
11.  IL-21 and T follicular helper cells 
International Immunology  2009;22(1):7-12.
Upon encounter with antigen, CD4+ T cells differentiate into effector Th subsets with distinctive functions that are related to their unique cytokine profiles and anatomical locations. One of the most important Th functions is to provide signals to developing B cells that induce specific and appropriate antibody responses. The major CD4+ T cell subset that helps B cells is the T follicular helper (TFH) cell, whose expression of the chemokine receptor CXCR5 [chemokine (C–X–C motif) receptor 5] serves to localize this cell to developing germinal centers (GCs) where it provides instructive signals leading to Ig class switching and somatic mutation. TFH cells produce high levels of IL-21, a cytokine that is critical for GC formation and also for the generation of TFH cells. Although TFH cells have been found to produce cytokines characteristic of other Th subsets, they represent a distinct lineage whose development is driven by the transcription factor B-cell CLL lymphoma-6 (BCL6). Consistent with their critical role in the generation of antibody responses, dysregulated TFH function has been associated with the development of systemic autoimmunity. Here, we review the role of IL-21 in the regulation of normal TFH development and function as well as in progression of autoimmune responses.
doi:10.1093/intimm/dxp112
PMCID: PMC2795365  PMID: 19933709
autoimmunity; BCL6; germinal center; Th subsets
12.  Cytokine Mediators of Th17 Function 
European journal of immunology  2009;39(3):658-661.
Th17 cells were identified as an independent lineage of CD4+ T cells that secrete a distinctive set of immunoregulatory cytokines, including IL-17A, IL-17F, IL-22, and IL-21. These cytokines collectively play roles in inflammation and autoimmunity and in the response to extracellular pathogens. The expression of the lineage-specific transcription factor RORγt leads to Th17 lineage commitment; however, it has become increasingly clear that the population of cells designated as Th17 cells is not homogeneous. Although these cells collectively produce characteristic Th17 cytokines, not all are produced by each individual cell in the population. The cytokines produced by individual cells are presumably affected in part by the specific local cytokine milieu. In this review, we discuss the current understanding of the specific functional characteristics and regulation of Th17 cytokines and clarify how they mediate the actions of Th17 cells.
doi:10.1002/eji.200839066
PMCID: PMC2735233  PMID: 19283717
13.  IL-21 mediates suppressive effects via its induction of IL-10* 
IL-21 is a pleiotropic cytokine that is required for normal immunoglobulin production. We previously showed that IL-21 was elevated in BXSB-Yaa mice with systemic lupus erythematosus. These mice also have elevated IL-10 levels, and we now show that IL-21 induces IL-10 mRNA and protein, suggesting unexpected immunosuppressive activities for IL-21. Indeed, Th1 priming with IL-21 leads to accumulation of cells with immunosuppressive activity, and IL-21 over-expression decreases specific antibody production after immunization in an IL-10-dependent fashion. Moreover, we show that IL-21 signaling is required for maximal induction of IL-10 by IL-6 or IL-27. Overall, our data indicate that IL-21 regulates immune responses at least in part by inducing IL-10 and reveal unanticipated immunosuppressive actions for this cytokine.
doi:10.4049/jimmunol.0802978
PMCID: PMC2756221  PMID: 19234181
14.  New insights into the regulation of T cells by γc family cytokines 
Nature reviews. Immunology  2009;9(7):480.
Preface
Common cytokine-receptor γ-chain (γc) family cytokines have critical roles in the development, proliferation, survival and differentiation of multiple cell lineages of both the innate and adaptive immune system. In this review, we focus on our current understanding of the distinct and overlapping effects of IL-2, IL-7, IL-9, IL-15, and IL-21, as well as the IL-7-related cytokine TSLP (thymic stromal lymphopoietin), on the survival and proliferation of conventional αβ T cells, γδ T cells, and regulatory T cells. This knowledge potentially allows for the therapeutic manipulation of immune responses for the treatment of cancer, autoimmunity, allergic diseases and immunodeficiency, as well as for vaccine development.
doi:10.1038/nri2580
PMCID: PMC2814538  PMID: 19543225
15.  The Yin and Yang of Interleukin-21 in Allergy, Autoimmunity and Cancer 
Current opinion in immunology  2008;20(3):295-301.
Summary
IL-21 is a type I cytokine that like IL-2, IL-4, IL-7, IL-9, and IL-15 shares the common cytokine receptor γ chain, γc. IL-21 is produced by activated CD4+ T cells, NKT cells, and Th17 cells, and has pleiotropic actions on a range of lymphoid lineages. IL-21 regulates immunoglobulin production and drives B-cell terminal differentiation into plasma cells, cooperatively expands CD8+ T cells and drives Th17 differentiation, has inhibitory effects on antigen-presentation by dendritic cells, and can be pro-apoptotic for B and NK cells. Moreover, IL-21 has potent anti-tumor effects and is implicated in the development of autoimmune diseases. Regulating IL-21 actions in vivo therefore has clinical potential for a range of diseases and is an area of active investigation.
doi:10.1016/j.coi.2008.02.004
PMCID: PMC2546604  PMID: 18554883
16.  A role for TSLP in the development of inflammation in an asthma model 
Thymic stromal lymphopoietin (TSLP) is a cytokine that promotes CD4+ T cell homeostasis. We now demonstrate that TSLP is required to mount a normal CD4+ T cell–mediated inflammatory response. TSLP acts directly on naive, but not, memory CD4+ T cells, and promotes their proliferation in response to antigen. In addition, TSLP exerts an effect indirectly through DCs to promote Th2 differentiation of CD4+ T cells. Correspondingly, TSLP receptor (TSLPR) knockout (KO) mice exhibit strong Th1 responses, with high levels of interleukin (IL)-12, interferon-γ, and immunoglobulin (Ig) G2a, but low production of IL-4, -5, -10, -13, and IgE; moreover, CD4+ T cells from these animals proliferate less well in response to antigen. Furthermore, TSLPR KO mice fail to develop an inflammatory lung response to inhaled antigen unless supplemented with wild-type CD4+ T cells. This underscores an important role for this cytokine in the development of inflammatory and/or allergic responses in vivo.
doi:10.1084/jem.20050199
PMCID: PMC2212950  PMID: 16172260
17.  Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function 
Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor γ chain (γc), which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44high) and naive (CD44low) phenotype CD8+ T cells and augment interferon-γ production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8+ T cells were impaired in IL-21R−/− mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8+ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8+ T cell expansion and effector function, primarily in a synergistic context with IL-15.
doi:10.1084/jem.20041057
PMCID: PMC2212766  PMID: 15630141
18.  A Role for Thymic Stromal Lymphopoietin in CD4+ T Cell Development 
Thymic stromal lymphopoietin (TSLP) signals via a receptor comprising the interleukin (IL)-7 receptor α chain and a distinctive subunit, TSLP receptor (TSLPR), which is most related to the common cytokine receptor γ chain, γc. We have generated TSLPR knockout (KO) mice and found that although these mice had normal lymphocyte numbers, γc/TSLPR double KO mice had a greater lymphoid defect than γc KO mice. This indicates that TSLP contributes to lymphoid development and accounts for some of the residual lymphoid development in γc KO mice and presumably in patients with X-linked severe combined immunodeficiency. Injection of TSLP into γc KO mice induced the expansion of T and B cells. Moreover, sublethally irradiated TSLPR KO mice showed weaker recovery of lymphocyte populations than wild-type (WT) littermates, even when neutralizing anti–IL-7 antibodies were injected. Interestingly, TSLP preferentially stimulated the proliferation and survival of CD4+ single positive thymocytes and peripheral T cells in vitro. Additionally, CD4+ T cells from TSLPR KO mice expanded less efficiently than WT CD4+ T cells in irradiated hosts, and TSLP preferentially expanded CD4+ T cells both in vitro and in vivo. Thus, as compared with other known cytokines, TSLP is distinctive in exhibiting a lineage preference for the expansion and survival of CD4+ T cells.
doi:10.1084/jem.20031975
PMCID: PMC2212020  PMID: 15263024
thymocyte development; IL-7; SCID; CD8 T cells; knockout mice
19.  Stat5 Synergizes with T Cell Receptor/Antigen Stimulation in the Development of Lymphoblastic Lymphoma 
Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8+ T cells, even in mice expressing a class II–restricted TCR transgene, with resulting CD8+ T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.
doi:10.1084/jem.20021548
PMCID: PMC2196089  PMID: 12835478
Stat5; TCR; lymphoma; DNA microarray; CD8+ T cell
20.  Essential Role of Signal Transducer and Activator of Transcription (Stat)5a but Not Stat5b for Flt3-Dependent Signaling 
The receptor tyrosine kinase Flt3 plays an important role in proliferation and survival of hematopoietic stem and progenitor cells. Although some post-receptor signaling events of Flt3 have been characterized, the involvement of the Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway in Flt3 signaling has not been thoroughly evaluated. To this aim, we examined whether Flt3 activates the Jak/Stat pathway in Baf3/Flt3 cells, a line stably expressing human Flt3 receptor. Stat5a, but not Stats 1–4, 5b, or 6, was potently activated by Flt3 ligand (FL) stimulation. Interestingly, FL did not activate any Jaks. Activation of Stat5a required the kinase activity of Flt3. A selective role for Stat5a in the proliferative response of primary hematopoietic progenitor cells to FL was documented, as FL did not act on progenitors from marrows of Stat5a−/− mice, but did stimulate/costimulate proliferation of these cells from Stat5a+/+, Stat5b−/−, and Stat5b+/+ mice. Thus, Stat5a is essential for at least certain effects of FL. Moreover, our data confirm that Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function.
PMCID: PMC2193267  PMID: 10974037
Flt3; signal transducer and activator of transfection 5; signal transduction; hematopoiesis; gene knockout

Results 1-20 (20)