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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-2 at the Crossroads of Effector Responses, Tolerance, and Immunotherapy 
Immunity  2013;38(1):13-25.
Interleukin-2 is a pleiotropic cytokine produced after antigen activation that plays pivotal roles in the immune response. Discovered as a T-cell growth factor, IL-2 additionally promotes CD8+ T cell and NK cell cytolytic activity, and modulates T cell differentiation programs in response to antigen, promoting naïve CD4+ T cell differentiation into T helper-1 (Th1) and T helper-2 (Th2) cells while inhibiting T helper-17 (Th17) and T follicular helper (Tfh) cell differentiation. Moreover, IL-2 is essential for the development and maintenance of T regulatory (Treg) cells and for activation-induced cell death, thereby mediating tolerance and limiting inappropriate immune reactions. In this review, we focus on the molecular mechanisms and complex cellular actions of IL-2, its cooperative and opposing effects with other cytokines, and how both promoting and blocking the actions of IL-2 are being utilized in clinical medicine.
doi:10.1016/j.immuni.2013.01.004
PMCID: PMC3610532  PMID: 23352221
4.  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
5.  TSLP: A Key Regulator of Asthma Pathogenesis 
Drug discovery today. Disease mechanisms  2012;9(3-4):10.1016/j.ddmec.2012.09.003.
Asthma is a complex disorder of the airways that is characterized by T helper type 2 (Th2) inflammation. The pleiotrophic cytokine TSLP has emerged as an important player involved in orchestrating the inflammation seen in asthma and other atopic diseases. Early research elucidated the role of TSLP on CD4+ T cells, and recent work has revealed the impact of TSLP on multiple cell types. Furthermore, TSLP plays an important role in the sequential progression of atopic dermatitis to asthma, clarifying the key role of TSLP in the pathogenesis of asthma, a finding with therapeutic implications.
doi:10.1016/j.ddmec.2012.09.003
PMCID: PMC3859144  PMID: 24348685
6.  Th17 cell-derived IL-17 is dispensable for B cell antibody production 
Cytokine  2012;59(1):108-114.
IL-17, which is preferentially produced by Th17 cells, is important for host defense against pathogens and is also involved in the development of autoimmune and allergic disorders. Antibody (Ab) production was shown to be impaired in IL-17-deficient mice, suggesting that IL-17 may promote B cell activation and direct secretion of Ab. However, the precise role of IL-17 in Ab production by B cells remains unclear. In the present study, we found constitutive expression of IL-17R in murine splenic B cells. Nevertheless, IL-17, IL-17F or IL-25 alone could not induce Ab production by B cells even in the presence of agonistic anti-CD40 Ab. IL-17 also could not affect IFN-γ-, IL-4- or TGF-β1-mediated Ig class-switching. Furthermore, in cocultures of B cells and IL-17−/− CD4+ T cells or IL-17−/− Th17 cells, IL-17 deficiency did not influence Ab production by B cells in vitro, suggesting that Th17 cell-derived IL-17 was not required for B cell Ab production through T-B cell interaction in vitro. Thus, in vivo, IL-17 may be indirectly involved in Ab production by enhancing production of B cell activator(s) by other immune cells.
doi:10.1016/j.cyto.2012.03.018
PMCID: PMC3746348  PMID: 22503615
interleukin-17; Th17 cells; B cells; antibody production
7.  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
8.  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
9.  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
10.  IL-21 Restricts Virus-driven Treg Cell Expansion in Chronic LCMV Infection 
PLoS Pathogens  2013;9(5):e1003362.
Foxp3+ regulatory T (Treg) cells are essential for the maintenance of immune homeostasis and tolerance. During viral infections, Treg cells can limit the immunopathology resulting from excessive inflammation, yet potentially inhibit effective antiviral T cell responses and promote virus persistence. We report here that the fast-replicating LCMV strain Docile triggers a massive expansion of the Treg population that directly correlates with the size of the virus inoculum and its tendency to establish a chronic, persistent infection. This Treg cell proliferation was greatly enhanced in IL-21R−/− mice and depletion of Treg cells partially rescued defective CD8+ T cell cytokine responses and improved viral clearance in some but not all organs. Notably, IL-21 inhibited Treg cell expansion in a cell intrinsic manner. Moreover, experimental augmentation of Treg cells driven by injection of IL-2/anti-IL-2 immune complexes drastically impaired the functionality of the antiviral T cell response and impeded virus clearance. As a consequence, mice became highly susceptible to chronic infection following exposure to low virus doses. These findings reveal virus-driven Treg cell proliferation as potential evasion strategy that facilitates T cell exhaustion and virus persistence. Furthermore, they suggest that besides its primary function as a direct survival signal for antiviral CD8+ T cells during chronic infections, IL-21 may also indirectly promote CD8+ T cell poly-functionality by restricting the suppressive activity of infection-induced Treg cells.
Author Summary
T cell exhaustion represents a state of T cell dysfunction associated with clinically relevant diseases, such as persistent viral infections or cancer. Although the molecular signature of exhausted T cells has been characterized in detail at the functional and transcriptional level, the immunological mechanisms that lead to T cell exhaustion during chronic infections remain poorly understood. Our present study reports two major findings that illustrate a pathway that contributes to T cell exhaustion during viral infection, and indicate its modulation by both, the pathogen and the host. First, we show that a persistence-inducing virus triggers the massive proliferation of Foxp3+ regulatory T (Treg) cells and demonstrate the potential of Treg cells to promote T cell exhaustion and chronic infection. Second, we identify IL-21 as a crucial host factor that antagonizes this virus-driven expansion of the Treg population in a cell intrinsic manner independent of IL-2. Thus, in addition to its known pre-dominant direct positive effects on antiviral T cells, IL-21 can also alleviate the suppressive activity of Treg cells. Together, these results suggest enhanced Treg cell responses as a mechanism of immune evasion that could be therapeutically targeted with IL-21.
doi:10.1371/journal.ppat.1003362
PMCID: PMC3656089  PMID: 23696736
11.  Compensatory dendritic cell development mediated by BATF-IRF interactions 
Nature  2012;490(7421):502-507.
The AP-1 transcription factor Batf3 is required for homeostatic development of CD8α+ classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here, we identify an alternative, Batf3-independent pathway for their development operating during infection with intracellular pathogens mediated by the cytokines IL-12 and IFN-γ. This alternative pathway results from molecular compensation for Batf3 provided by the related AP-1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiologic compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA-4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP-1 factors such as Irf4 and Irf8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.
doi:10.1038/nature11531
PMCID: PMC3482832  PMID: 22992524
12.  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
13.  Critical Role of STAT5 Transcription Factor Tetramerization for Cytokine Responses and Normal Immune Function 
Immunity  2012;36(4):586-599.
Summary
Cytokine-activated STAT proteins dimerize and bind to high-affinity motifs, and N-terminal domain-mediated oligomerization of dimers allows tetramer formation and binding to low-affinity tandem motifs, but the functions of dimers versus tetramers are unknown. We generated Stat5a-Stat5b double knock-in (DKI) N-domain mutant mice that form dimers but not tetramers, identified cytokine-regulated genes whose expression required STAT5 tetramers, and defined dimer versus tetramer consensus motifs. Whereas Stat5- deficient mice exhibited perinatal lethality, DKI mice were viable; thus, STAT5 dimers were sufficient for survival. Nevertheless, STAT5 DKI mice had fewer CD4+CD25+ T cells, NK cells, and CD8+ T cells, with impaired cytokine-induced and homeostatic proliferation of CD8+ T cells. DKI CD8+ T cell proliferation following viral infection was diminished and DKI Treg cells did not efficiently control colitis. Thus, tetramerization of STAT5 is dispensable for survival but is critical for cytokine responses and normal immune function, establishing a critical role for tetramerization in vivo.
doi:10.1016/j.immuni.2012.02.017
PMCID: PMC3551341  PMID: 22520852
14.  CREB/ATF-dependent T cell receptor–induced FoxP3 gene expression: a role for DNA methylation 
The Journal of Experimental Medicine  2007;204(7):1543-1551.
Regulatory T cells (T reg cells) are a population of CD4+ T cells that limit immune responses. FoxP3 is a master control transcription factor for development and function of these cells, but its regulation is poorly understood. We have identified a T cell receptor–responsive enhancer in the FoxP3 first intron that is dependent on a cyclic-AMP response element binding protein (CREB)/activating transcription factor (ATF) site overlapping a CpG island. Methylation of this island inversely correlates with CREB binding and FoxP3 expression. Interestingly, transforming growth factor-β, which induces T reg cell formation, decreases methylation of the CpG island and increases FoxP3 expression. Similarly, inhibiting methylation with 5-azacytidine or knocking down the DNA methyltransferase Dnmt1 also induces FoxP3 expression. Conversely, methylation of the CpG island, which decreases CREB binding or expression of dominant-negative CREB, decreases FoxP3 gene expression. Thus, T cell receptor–induced FoxP3 expression in T reg cells is controlled both by sequence-specific binding of CREB/ATF and by DNA methylation of a CpG island.
doi:10.1084/jem.20070109
PMCID: PMC2118651  PMID: 17591856
15.  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
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.  Induction of Thymic Stromal Lymphopoietin Production by Xylene and Exacerbation of Picryl Chloride-Induced Allergic Inflammation in Mice 
Background
Some chemical compounds in the environment worsen allergic inflammation. In this study, we examined whether organic solvents induce the production of thymic stromal lymphopoietin (TSLP) which elicits Th2-type immune responses.
Methods
Organic solvents were painted on the earlobes of BALB/c mice. The expression of TSLP in the ear was determined by ELISA.
Results
Xylene and toluene, but not chloroform or ethyl acetate, induced the expression of mRNA for TSLP in the earlobe tissue. Among the aromatic compounds, xylene, especially m-xylene, and trimethylbenzene caused apparent TSLP production. The level of TSLP in the xylene-treated earlobes reached a maximum at 24 h, and TSLP was expressed in epithelial tissues. Production of TSLP was unaffected in mast cell-deficient W/Wv mice but apparently diminished in TNF-α knockout mice and IL-4 receptor knockout mice. Repeated painting of xylene for 7 days induced an increase in the weight of cervical lymph nodes and expression of OX40 ligand, both of which were inhibited in TSLP receptor knockout mice. Xylene promoted the picryl chloride-induced thickening of the ear and IL-4 production, which were reversed in TSLP receptor knockout mice.
Conclusion
Xylene induced TSLP production, resulting in an exacerbation of allergic inflammation. Thus, xylene might be a good tool for examining the roles of TSLP in eliciting allergy in experimental animals.
doi:10.1159/000327545
PMCID: PMC3221269  PMID: 21986191
Allergic inflammation; Thymic stromal lymphopoietin; Xylene
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.  IL-21 Is an Antitolerogenic Cytokine of the Late-Phase Alloimmune Response 
Diabetes  2011;60(12):3223-3234.
OBJECTIVE
Interleukin-21 (IL-21) is a proinflammatory cytokine that has been shown to affect Treg/Teff balance. However, the mechanism by which IL-21 orchestrates alloimmune response and interplays with Tregs is still unclear.
RESEARCH DESIGN AND METHODS
The interplay between IL-21/IL-21R signaling, FoxP3 expression, and Treg survival and function was evaluated in vitro in immunologically relevant assays and in vivo in allogenic and autoimmune models of islet transplantation.
RESULTS
IL-21R expression decreases on T cells and B cells in vitro and increases in the graft in vivo, while IL-21 levels increase in vitro and in vivo during anti-CD3/anti-CD28 stimulation/allostimulation in the late phase of the alloimmune response. In vitro, IL-21/IL-21R signaling (by using rmIL-21 or genetically modified CD4+ T cells [IL-21 pOrf plasmid–treated or hIL-21-Tg mice]) enhances the T-cell response during anti-CD3/anti-CD28 stimulation/allostimulation, prevents Treg generation, inhibits Treg function, induces Treg apoptosis, and reduces FoxP3 and FoxP3-dependent gene transcripts without affecting FoxP3 methylation status. In vivo targeting of IL-21/IL-21R expands intragraft and peripheral Tregs, promotes Treg neogenesis, and regulates the antidonor immune response, whereas IL-21/IL-21R signaling in Doxa-inducible ROSA-rtTA-IL-21-Tg mice expands Teffs and FoxP3− cells. Treatment with a combination of mIL-21R.Fc and CTLA4-Ig (an inhibitor of the early alloimmune response) leads to robust graft tolerance in a purely alloimmune setting and prolonged islet graft survival in NOD mice.
CONCLUSIONS
IL-21 interferes with different checkpoints of the FoxP3 Treg chain in the late phase of alloimmune response and, thus, acts as an antitolerogenic cytokine. Blockade of the IL-21/IL-21R pathway could be a precondition for tolerogenic protocols in transplantation.
doi:10.2337/db11-0880
PMCID: PMC3219943  PMID: 22013017
20.  Stat5b Is Essential for Natural Killer Cell–mediated Proliferation and Cytolytic Activity  
The Journal of Experimental Medicine  1998;188(11):2067-2074.
We have analyzed the immune system in Stat5-deficient mice. Although Stat5a−/− splenocytes have a partial defect in anti-CD3-induced proliferation that can be overcome by high dose interleukin (IL)-2, we now demonstrate that defective proliferation in Stat5b−/− splenocytes cannot be corrected by this treatment. Interestingly, this finding may be at least partially explained by diminished expression of the IL-2 receptor β chain (IL-2Rβ), which is a component of the receptors for both IL-2 and IL-15, although other defects may also exist. Similar to the defect in proliferation in activated splenocytes, freshly isolated splenocytes from Stat5b−/− mice exhibited greatly diminished proliferation in response to IL-2 and IL-15. This results from both a decrease in the number and responsiveness of natural killer (NK) cells. Corresponding to the diminished proliferation, basal as well as IL-2– and IL-15–mediated boosting of NK cytolytic activity was also greatly diminished. These data indicate an essential nonredundant role for Stat5b for potent NK cell–mediated proliferation and cytolytic activity.
PMCID: PMC2212377  PMID: 9841920
natural killer cells; Stat5b; Stat5a; interleukin 2; interleukin 15
21.  The Common Cytokine Receptor γ Chain Plays an Essential Role in Regulating Lymphoid Homeostasis 
In the immune system, there is a careful regulation not only of lymphoid development and proliferation, but also of the fate of activated and proliferating cells. Although the manner in which these diverse events are coordinated is incompletely understood, cytokines are known to play major roles. Whereas IL-7 is essential for lymphoid development, IL-2 and IL-4 are vital for lymphocyte proliferation. The receptors for each of these cytokines contain the common cytokine receptor γ chain (γc), and it was previously shown that γc-deficient mice exhibit severely compromised development and responsiveness to IL-2, IL-4, and IL-7. Nevertheless, these mice exhibit an age-dependent accumulation of splenic CD4+ T cells, the majority of which have a phenotype typical of memory/activated cells. When γc-deficient mice were mated to DO11.10 T cell receptor (TCR) transgenic mice, only the T cells bearing endogenous TCRs had this phenotype, suggesting that its acquisition was TCR dependent. Not only do the CD4+ T cells from γc-deficient mice exhibit an activated phenotype and greatly enhanced incorporation of bromodeoxyuridine but, consistent with the lack of γc-dependent survival signals, they also exhibit an augmented rate of apoptosis. However, because the CD4+ T cells accumulate, it is clear that the rate of proliferation exceeds the rate of cell death. Thus, surprisingly, although γc-independent signals are sufficient to mediate expansion of CD4+ T cells in these mice, γc-dependent signals are required to regulate the fate of activated CD4+ T cells, underscoring the importance of γc-dependent signals in controlling lymphoid homeostasis.
PMCID: PMC2196113  PMID: 9016868
22.  IL-2 Family Cytokines: New Insights into the Complex Roles of IL-2 as a Broad Regulator of T helper Cell Differentiation 
Current Opinion in Immunology  2011;23(5):598-604.
Interleukin-2 (IL-2) is a pleiotropic cytokine that drives T-cell growth, augments NK cytolytic activity, induces the differentiation of regulatory T cells, and mediates activation-induced cell death. Along with IL-4, IL-7, IL-9, IL-15, and IL-21, IL-2 shares the common cytokine receptor γ chain, γc, which is mutated in humans with X-linked severe combined immunodeficiency. Herein, we primarily focus on the recently discovered complex roles of IL-2 in broadly modulating T cells for T helper cell differentiation. IL-2 does not specify the type of Th differentiation that occurs; instead, IL-2 modulates expression of receptors for other cytokines and transcription factors, thereby either promoting or inhibiting cytokine cascades that correlate with each Th differentiation state. In this fashion, IL-2 can prime and potentially maintain Th1 and Th2 differentiation as well as expand such populations of cells, whereas it inhibits Th17 differentiation but also can expand Th17 cells.
doi:10.1016/j.coi.2011.08.003
PMCID: PMC3405730  PMID: 21889323
23.  Thymic stromal lymphopoietin is a key mediator of breast cancer progression 
Inflammation is a double-edged sword that can promote or suppress cancer progression. Here we report that thymic stromal lymphopoietin (TSLP), an IL-7-like type 1 inflammatory cytokine that is often associated with the induction of Th2-type allergic responses in the lungs, is also expressed in human and murine cancers. Our studies with murine cancer cells indicate that TSLP plays an essential role in cancer escape, as its inactivation in cancer cells alone was sufficient to almost completely abrogate cancer progression and lung metastasis. The cancer-promoting activity of TSLP primarily required signaling through the TSLP receptor on CD4+ T cells, promoting Th2-skewed immune responses and production of immunosuppressive factors such as IL-10 and IL-13. Expression of TSLP therefore may be a useful prognostic marker and its targeting could have therapeutic potential.
doi:10.4049/jimmunol.1100463
PMCID: PMC3401482  PMID: 21490155
TSLP; breast cancer metastasis; Th2-type responses
24.  IL-13 Induces Skin Fibrosis in Atopic Dermatitis by Thymic Stromal Lymphopoietin 
Skin fibrotic remodeling is a major feature in human atopic dermatitis (AD). Inflammation and tissue fibrosis are common consequences of Th2 responses. Elevated IL-13 and thymic stromal lymphopoietin (TSLP) have been found in the AD skin lesions. Fibrocytes can be recruited to inflamed tissues to promote wound healing and fibrosis. Dermal transgenic expression of IL-13 causes an AD-like phenotype with fibrosis and increased TSLP. However, the role of TSLP in fibrotic remodeling is unknown. In this study, we investigated the role of TSLP and fibrocytes in the generation of IL-13–induced skin fibrosis. In AD lesion, cessation of IL-13 transgene expression resulted in reduced skin inflammation but with no effect on further progression of fibrosis. This was accompanied by markedly increased CD34+/procollagen 1+ fibrocytes. Furthermore, fibrocytes express TSLP receptor (TSLPR), and TSLP directly promotes PBMC-derived fibrocytes to produce collagen. Neutralization of TSLP or genetic deletion of TSLPR in IL-13 transgenic mice resulted in a significant reduction in fibrocytes and in skin fibrosis. Furthermore, reduction of fibrosis by depletion of TSLP was independent of IL-13. Interestingly, the number of fibrocytes was highly increased in the skin samples of AD patients. These data indicate that the progression of skin fibrosis in IL-13–induced AD occurs via TSLP/TSLPR-dependent but IL-13–independent novel mechanisms by promoting fibrocyte functions.
doi:10.4049/jimmunol.1100504
PMCID: PMC3399513  PMID: 21576506
25.  Unusual Timing of CD127 Expression by Mouse Uterine Natural Killer Cells 
Journal of Leukocyte Biology  2012;91(3):417-426.
Decidualization, a progesterone-dependent process that alters endometrial stromal cells at implantation sites in humans and rodents, is accompanied by a highly regulated, NK cell-dominated, leukocyte influx into decidua basalis (DB). Whether uterine NK cells differentiate from uterine progenitor cells is unknown as are the mechanisms restricting leukocytes to DB. We asked if cells expressing the early NK lineage marker CD127 (IL-7Rα) occurred in mouse decidua. CD127 was absent from gestation day (gd)6.5 decidual lymphoid cells but became expressed by a mature uNK cell subset in gd10.5 DB. DB and transient myometrial structures (MLAp) that ring maternal blood vessels supplying placentae both expressed IL-7 and thymic stromal lymphopoietin (TSLP), the CD127 ligands, but with differing temporal and spatial patterns. Uterine NK cells expressed TSLPR and study of gd10.5 implantation sites from mice deleted for IL-7, CD127 or TSLPR suggested that IL-7 and its receptor have physiological roles in limiting expansion of immature uNK cells within MLAp while the TSLP signalling pathway is used in DB to sustain IFN-γ production from a subset of mature uNK cells. Regionalized, dynamic expression of the additional lymphoid organ stromal markers gp38/Podoplanin and ER-TR7 but not CD157 was seen by immunohistochemistry in implantation sites and DB and MLAp contained transcripts for Aire, a tolerance54 promoting factor. These observations suggest that CD127+ NK lineage progenitors are not present in the early postimplantation period of mouse uterus and that decidualized endometrial stroma has key immunoregulatory properties.
doi:10.1189/jlb.1011501
PMCID: PMC3289395  PMID: 22227963 CAMSID: cams2039
Decidua; interleukin 7; stromal factor; thymic stromal lymphopoietin

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