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1.  IL-27, targeting antigen presenting cells, promotes Th17 differentiation and colitis in mice 
Mucosal immunology  2013;7(3):625-633.
Th17 cells have been implicated in autoimmunity and inflammatory bowel disease (IBD). Antigen presenting cell (APC) derived cytokines such as IL-1β and IL-6 are key mediators supporting Th17 differentiation, yet how these factors are induced in vivo remains unclear. Here we show that IL-27 acting on APCs enhances IL-6 and IL-1β production and Th17 differentiation. IL-27Rα−/− TCRβ−/− recipients fail to develop gut inflammation following naïve CD4 T cell transfer, while IL-27Rα+/+ TCRβ−/− recipients develop severe colitis. Investigation of T cell responses exhibits that IL-27Rα−/− TCRβ−/− mice do not support Th17 differentiation with significantly decreased levels of IL-6 and IL-1β by APCs. Our study has identified a novel proinflammatory role for IL-27 in vivo that promotes Th17 differentiation by inducing Th17-supporting cytokines in APCs.
doi:10.1038/mi.2013.82
PMCID: PMC3989480  PMID: 24129161
CD4; APC; IBD
2.  Spontaneous Proliferation of H2M-/- CD4 T Cells Results in Unusual Acute Hepatocellular Necrosis 
PLoS ONE  2014;9(10):e110516.
Naïve CD4 T cells are triggered to undergo spontaneous proliferation, a proliferative response induced in response to homeostatic stimulation, when exposed to severe lymphopenic environments. They spontaneously acquire proinflammatory effector phenotypes, playing a major role in inducing chronic inflammation in the intestine that is believed to be induced by T cell recognition of commensal antigens. While the antigens inducing the T cell responses and inflammation are being extensively investigated, the role of clonality of T cells involved in this process remains poorly understood. In this study, we utilized naïve CD4 T cells isolated from B6 H2M−/− mice, in which MHCII molecules are complexed with a single CLIP molecule, and examined spontaneous proliferation and intestinal inflammation of CD4 T cells expressing limited T cell receptor repertoire diversity. We found that H2M−/− CD4 T cells undergo robust spontaneous proliferation, differentiate into IFNγ-producing Th1 type effector cells, and, most unexpectedly, induce severe acute hepatocellular necrosis. T cell interaction with MHCII molecule on cells of hematopoietic origin was essential to induce the pathology. Interestingly, B cells are fully capable of preventing necrotic inflammation via IL-10-independent and B7-H1-dependent mechanism. This could be a useful animal model to examine T cell-mediated liver inflammation and B cell-mediated immune regulation.
doi:10.1371/journal.pone.0110516
PMCID: PMC4196993  PMID: 25313460
3.  Cellular Factors Targeting APCs to Modulate Adaptive T Cell Immunity 
Journal of Immunology Research  2014;2014:750374.
The fate of adaptive T cell immunity is determined by multiple cellular and molecular factors, among which the cytokine milieu plays the most important role in this process. Depending on the cytokines present during the initial T cell activation, T cells become effector cells that produce different effector molecules and execute adaptive immune functions. Studies thus far have primarily focused on defining how these factors control T cell differentiation by targeting T cells themselves. However, other non-T cells, particularly APCs, also express receptors for the factors and are capable of responding to them. In this review, we will discuss how APCs, by responding to those cytokines, influence T cell differentiation and adaptive immunity.
doi:10.1155/2014/750374
PMCID: PMC4122108  PMID: 25126585
4.  Colitogenic effector T cells: roles of gut homing integrin, gut antigen specificity, and γδ T cells 
Immunology and cell biology  2013;92(1):90-98.
Disturbance of T cell homeostasis could lead to intestinal inflammation. Naïve CD4 T cells undergoing spontaneous proliferation, a robust proliferative response that occurs under severe lymphopenic conditions, differentiate into effector cells producing Th1 and/or Th17 type cytokines and induce a chronic inflammation in the intestine that resembles human inflammatory bowel disease. In this study, we investigated key properties of CD4 T cells necessary to induce experimental colitis. α4β7 upregulation was primarily induced by mLN resident CD11b+ dendritic cell subsets via TGFβ/retinoic acid-dependent mechanism. Interestingly, α4β7 expression was essential but not sufficient to induce inflammation. In addition to gut homing specificity, expression of gut Ag specificity was also crucial. T cell acquisition of the specificity was dramatically enhanced by the presence of γδ T cells, a population previously shown to exacerbate T cell mediated colitis. Importantly, IL-23-mediated γδ T cell stimulation was necessary to enhance colitogenicity but not gut antigen reactivity of proliferating CD4 T cells. These findings demonstrate that T cell colitogenicity is achieved through multiple processes, offering a therapeutic rationale by intervening these pathways.
doi:10.1038/icb.2013.70
PMCID: PMC3947309  PMID: 24189163
α4β7 integrin; CD4 T cells; colitis; gut antigens; IBD
5.  IL-4 Derived from Non-T Cells Induces Basophil- and IL-3-independent Th2 Immune Responses 
Immune Network  2013;13(6):249-256.
How Th2 immunity develops in vivo remains obscure. Basophils have been considered key innate cells producing IL-4, a cytokine essential for Th2 immunity. Increasing evidence suggests that basophils are dispensable for the initiation of Th2 immunity. In this study, we revisited the role of basophils in Th2 immune responses induced by various types of adjuvants. Mice deficient in IL-3 or IL-3 receptor, in which basophil lymph node recruitment is completely abolished, fully developed wild type level Th2 CD4 T cell responses in response to parasite antigen or papain immunization. Similar finding was also observed in mice where basophils are inducibly ablated. Interestingly, IL-4-derived from non-T cells appeared to be critical for the generation of IL-4-producing CD4 T cells. Other Th2 promoting factors including IL-25 and thymic stromal lymphopoietin (TSLP) were dispensable. Therefore, our results suggest that IL-3- and basophil-independent in vivo Th2 immunity develops with the help of non-T cell-derived IL-4, offering an additional mechanism by which Th2 type immune responses arise in vivo.
doi:10.4110/in.2013.13.6.249
PMCID: PMC3875783  PMID: 24385943
Basophils; Papain; Parasites; Th2 immunity
6.  Epithelial cell-specific Act1 adaptor mediates interleukin-25-dependent helminth expulsion through expansion of Lin−c-Kit+ innate cell population 
Immunity  2012;36(5):821-833.
SUMMARY
Interleukin-25 (IL-25 or IL-17E), a member of the structurally related IL-17 family, functions as an important mediator of T helper 2 cell-type (type 2) responses. We examined the cell-type specific role of IL-25-induced Act1-mediated signaling in protective immunity against helminth infection. Targeted Act1 deficiency in epithelial cells resulted in a marked delay in worm expulsion and abolished the expansion of the Lin−c-kit+ innate cell population in the mesenteric lymph node, lung and liver. Th2 cell-inducing cytokines (IL-25 and IL-33) expression were reduced in the intestinal epithelial cells from the infected and IL-25-injected epithelial-specific Act1-deficient mice. Adoptive transfer of Lin−c-kit+ cells or combined injection of IL-25 and IL-33 restored the type 2 responses in these mice. Taken together, these results suggest that epithelial-specific Act1 mediates the expansion of the Lin−c-kit+ innate cell population through the positive feedback loop of IL-25, initiating the type 2 immunity against helminth infection.
doi:10.1016/j.immuni.2012.03.021
PMCID: PMC3376903  PMID: 22608496
7.  Memory CD4 T cells induce selective expression of IL-27 in CD8+ DC and regulate homeostatic naïve T cell proliferation 
Naïve T cells undergo robust proliferation in lymphopenic conditions, while they remain quiescent in steady-state conditions. However, a mechanism by which naïve T cells are kept from proliferating under steady-state conditions remains unclear. Here we report that memory CD4 T cells are able to limit naïve T cell proliferation within lymphopenic hosts by modulating stimulatory functions of DC. The inhibition was mediated by IL-27, which was primarily expressed in CD8+ DC subsets as the result of memory CD4 T cell-DC interaction. IL-27 appeared to be the major mediator of inhibition as naïve T cells deficient in IL-27R were resistant to memory CD4 T cell mediated inhibition. Finally, IL-27-mediated regulation of T cell proliferation was also observed in steady-state conditions as well as during Ag-mediated immune responses. We propose a new model for maintaining peripheral T cell homeostasis via memory CD4 T cells and CD8+ DC-derived IL-27 in vivo.
doi:10.4049/jimmunol.1101908
PMCID: PMC3244513  PMID: 22116827
8.  Both exogenous commensal and endogenous self antigens stimulate T cell proliferation under lymphopenic conditions 
Cellular immunology  2011;272(2):117-123.
Within lymphopenic recipients, naïve T cells undergo proliferation that is induced by homeostatic mechanisms. Earlier studies have demonstrated that commensal antigens play a key role in inducing the proliferation. However, a relative contribution of endogenous self antigens in this process has not been formally investigated. In this study, we utilized a pharmacologic inhibitor that blocks T cell egress from the lymphoid tissues, antibiotics, and germ-free animals to examine the role of commensal and self antigens. The results suggest that T cell proliferation under lymphopenic conditions is a heterogeneous process triggered by both exogenous commensal and endogenous self antigens.
doi:10.1016/j.cellimm.2011.11.002
PMCID: PMC3244518  PMID: 22169530
homeostasis; T cell; commensal antigen; FTY720; self antigen; lymphopenia
9.  Basophils are the Major Producers of IL-4 During Primary Helminth Infection 
IL-4 production by leukocytes is a key regulatory event that occurs early in the type-2 immune response, which induces allergic reactions and mediates expulsion of parasites. CD4+ T-cells and basophils are thought to be the key cell types that produce IL-4 during a type-2 response. Here, we assessed the relative contribution of both CD4+ T-cell- and basophil-IL-4 production during primary and secondary responses to Nippostrongylus brasiliensis using a murine IL-4-eGFP reporter system. During infection, IL-4 producing basophils were detected systemically and tissue recruitment occurred independent of IL-4/STAT6 signaling. We observed that basophil recruitment to a tissue environment was required for their full activation. Basophil induction in response to secondary infection exhibited accelerated kinetics in comparison to primary infection. However, total basophil numbers were not enhanced, as predicted by previous models of protective immunity. Overall, the induction and migration of IL-4 producing basophils into peripheral tissues was found to be a prominent characteristic of the primary, but not memory responses to N. brasiliensis infection where CD4+ T-cells were identified as the major source of IL-4. While basophils were the major initial producers of IL-4 we determined that normal TH2 differentiation occurs independently of basophils and depletion of basophils led to an enhancement of inflammatory cell recruitment to the site of infection.
doi:10.4049/jimmunol.1000940
PMCID: PMC3488853  PMID: 21270410
10.  BASOPHILS, IgE AND AUTOANTIBODY-MEDIATED KIDNEY DISEASE 
Basophils are of interest in immunology due to their ability to produce a Th2-signature cytokine, IL-4, following activation. New understanding of the role of basophils in immunity shows novel functions at a cellular level through which basophils influence adaptive immunity. This review summarizes new advances in basophil biology and discusses new roles for basophils in human disease, especially in the mediation of the pathogenesis of lupus nephritis. Recently, basophils have been shown to contribute to self-reactive antibody production in systemic lupus erythematosus and may enhance pre-existing loss of B cell tolerance, suggesting that basophils, IL-4 and IgE mediate the pathogenesis of lupus nephritis by promoting the Th2 environment and activating autoreactive B cells. In addition to envisaging exciting therapeutic prospects, these novel findings open the way for the study of basophils in other autoimmune and renal diseases.
doi:10.4049/jimmunol.1002648
PMCID: PMC3466044  PMID: 21597041
11.  CD4 T cells play important roles in maintaining IL-17-producing γδ T cell subsets in naïve animals 
Immunology and Cell Biology  2011;90(4):396-403.
A proportional balance between αβ and γδ T cell subsets in the periphery is exceedingly well maintained via a homeostatic mechanism. However, a cellular mechanism underlying the regulation remains undefined. We recently reported that a subset of developing γδ T cells spontaneously acquire IL-17-producing capacity even within naïve animals via a TGFβ1-dependent mechanism, thus considered ‘einnate’ IL-17-producing cells. Here we report that γδ T cells generated within αβ T cell (or CD4 T cell)-deficient environments displayed altered cytokine profiles; particularly, ‘einnate’ IL-17 expression was significantly impaired compared to those in wild type mice. Impaired IL-17 production in γδ T cells was directly related to the CD4 T cell deficiency, because depletion of CD4 T cells in wild type mice diminished and adoptive CD4 T cell transfer into TCRβ−/− mice restored IL-17 expression in γδ T cells. CD4 T cell-mediated IL-17 expression required TGFβ1. Moreover, Th17 but not Th1 or Th2 effector CD4 T cells were highly efficient in enhancing γδ T cell IL-17 expression. Taken together, our results highlight a novel CD4 T cell-dependent mechanism that shapes the generation of IL-17+ γδ T cells in naïve settings.
doi:10.1038/icb.2011.50
PMCID: PMC3170686  PMID: 21647171
CD4 T cells; γδ T cells; IL-17; TGFβ1
12.  CD4 T Cells Promote CD8 T Cell Immunity at the Priming and Effector Site during Viral Encephalitis 
Journal of Virology  2012;86(5):2416-2427.
CD4 T cell activation during peripheral infections not only is essential in inducing protective CD8 T cell memory but also promotes CD8 T cell function and survival. However, the contributions of CD4 T cell help to antiviral CD8 T cell immunity during central nervous system (CNS) infection are not well established. Encephalitis induced by the sublethal coronavirus JHMV was used to identify when CD4 T cells regulate CD8 T cell responses following CNS infection. Peripheral expansion of virus-specific CD8 T cells was impaired when CD4 T cells were ablated prior to infection but not at 4 days postinfection. Delayed CD4 T cell depletion abrogated CD4 T cell recruitment to the CNS but only slightly diminished CD8 T cell recruitment. Nevertheless, the absence of CNS CD4 T cells was associated with reduced gamma interferon (IFN-γ) and granzyme B expression by infiltrating CD8 T cells, increased CD8 T cell apoptosis, and impaired control of infectious virus. CD4 T cell depletion subsequent to CD4 T cell CNS migration restored CD8 T cell activity and virus control. Analysis of γc-dependent cytokine expression indicated interleukin-21 (IL-21) as a primary candidate optimizing CD8 T cell activity within the CNS. These results demonstrate that CD4 T cells play critical roles in both enhancing peripheral activation of CD8 T cells and prolonging their antiviral function within the CNS. The data highlight the necessity for temporally and spatially distinct CD4 T cell helper functions in sustaining CD8 T cell activity during CNS infection.
doi:10.1128/JVI.06797-11
PMCID: PMC3302259  PMID: 22205741
13.  BASOPHILS AND TYPE 2 IMMUNITY 
Current Opinion in Hematology  2008;15(1):59-63.
Purpose of review
Mechanisms involved in the development of in-vivo type 2 immunity are poorly defined. Basophils are potent IL-4-producing cells and may contribute to the process of polarizing immune responses.
Recent findings
Although basophils represent fewer than 0.5% of blood leukocytes, their frequency dramatically increases under certain circumstances, particularly Th2-related responses including parasitic infection and allergic inflammation. Recent studies proposed the hypothesis that basophils could contribute to the development of type 2 immunity by providing initial IL-4 important in T cell polarization and by recruiting other effector cells such as eosinophils or neutrophils. Multiple stimuli of IgE-dependent and IgE-independent pathways that lead to release of cytokines and mediators from activated basophils have been identified. In addition, progenitors that differentiate into mature basophils have recently been identified.
Summary
The current review revisits basophils with the goal of providing insights into understanding unappreciated roles of basophils in vivo.
doi:10.1097/MOH.0b013e3282f13ce8
PMCID: PMC3403736  PMID: 18043247
basophils; IL-4; parasites; Th2 type immunity
14.  Generation of colitogenic Th17 CD4 T cells is enhanced by IL-17+γδ T cells 
Th17 cells have been implicated in the pathogenesis of colitis; however, a cellular mechanism by which colitogenic Th17 immunity arises in vivo remains unclear. In this study, we report that a subset of IL-17+γδ T cells plays a crucial role in enhancing in vivo Th17 differentiation and T cell-mediated colitis. TCRβ-/- mice were highly susceptible to T cell-mediated colitis, while TCRβδ-/- mice were resistant to the disease. Importantly, cotransfer of IL-17+ but not of IL-17-γδ T cells with CD4 T cells was sufficient to enhance Th17 differentiation and induce full-blown colitis in TCRβδ-/- recipients. Collectively, our results provide a novel function of IL-17+γδ T cell subsets in supporting in vivo Th17 differentiation and possibly in fostering the development of intestinal inflammation.
doi:10.4049/jimmunol.1004021
PMCID: PMC3200541  PMID: 21402889
colitis; γδ T cells; IL-17; Th17 CD4 T cells
15.  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
16.  Basophils are transiently recruited into the draining lymph nodes during helminth infection via IL-3 but infection-induced Th2 immunity can develop without basophil lymph node recruitment or IL-31 
Basophils are recognized as immune modulators through their ability to produce IL-4, a key cytokine required for Th2 immunity. It has also recently been reported that basophils are transiently recruited into the draining LN after allergen immunization and that the recruited basophils promote the differentiation of naïve CD4 T cells into Th2 effector cells. Using IL-3-/- and IL-3Rβ-/- mice, we report here that the IL-3/IL-3R system is absolutely required to recruit circulating basophils into the draining LN following helminth infection. Unexpectedly, the absence of IL-3 or of basophil LN recruitment played little role in helminth-induced Th2 immune responses. Moreover, basophil depletion in infected mice did not diminish the development of IL-4-producing CD4 T cells. Taken together, our results reveal a previously unknown role of IL-3 in recruiting basophils to the LN and demonstrate that basophils are not necessarily associated with the development of Th2 immunity during parasite infection.
doi:10.4049/jimmunol.0902447
PMCID: PMC2849628  PMID: 20038645
basophils; CD4 T cells; IL-3; parasites; Th2 immunity
17.  Mice that “conditionally” lack basophils, AT LAST 
The Journal of Clinical Investigation  2010;120(8):2648-2651.
Basophils are the least abundant granulocytes found in the circulation. Until recently, their functions were poorly understood. In the past few years, the list of basophil functions in the context of immunity has dramatically increased. Thus, the need for basophil-deficient animal models to confirm these findings is imperative. In this issue of the JCI, Wada and colleagues introduce the first mouse model in which basophils are conditionally ablated in vivo. Using this model, they then uncover a nonredundant role for basophils in acquired immunity against tick infection.
doi:10.1172/JCI44058
PMCID: PMC2912205  PMID: 20664167
18.  Basophils induce Th2 immunity 
Virulence  2010;1(5):399-401.
Despite the fact that basophils represent less than 0.5% of circulating leukocytes, recent studies have begun to unveil their potent immunoregulatory functions, i.e., induction of Th2 immunity. It is believed that basophils are capable of doing so primarily by secreting key Th2-inducing cytokines, namely IL-4 and Thymic Stromal Lymphopoietin (TSLP), and by functioning as professional antigen presenting cells. However, we have recently demonstrated that Th2 immunity can develop in the absence of basophils or IL-4 during helminth infection. In this review, how basophils may (and may not) contribute to the development of Th2 immunity in vivo is discussed.
doi:10.4161/viru.1.5.12550
PMCID: PMC3073173  PMID: 21178477
basophils; CD4 T cells; IL-3; Nippostrongylus brasiliensis; Th2 immunity
19.  The essential role of SIGIRR/TIR8 in regulation of Th2 immune response1 
A novel cytokine IL-33, an IL-1 family member, signals via ST2 receptor and promotes T helper type 2 (Th2) responses, through the activation of NFκB and MAP kinases. Previous studies reported that SIGIRR (single immunoglobulin IL-1R-related molecule)/TIR8 (Toll IL-1R8) acts as negative regulator for TLR-IL-1R-mediated signaling. We now found that SIGIRR formed a complex with ST2 upon IL-33 stimulation and specifically inhibited IL-33/ST2-mediated signaling in cell culture model. Furthermore, IL-33-induced Th2 response was enhanced in SIGIRR-deficient mice compared to that in wild-type control mice, suggesting a negative regulatory role of SIGIRR in IL-33/ST2 signaling in vivo. Similar to ST2, SIGIRR was highly expressed in in vitro polarized Th2 cells, but not Th1 cells. SIGIRR-deficient Th2 cells produce higher levels of “Th2 cytokines”, including IL-5, IL-4 and IL-13 than that in wild-type cells. Moreover, SIGIRR-deficient mice developed stronger Th2 immune response in OVA-challenged asthma model. Taken together, our results suggest that SIGIRR plays an important role in the regulation of Th2 response in vivo, possibly through its impact on IL-33-ST2-mediated signaling.
doi:10.4049/jimmunol.0802729
PMCID: PMC2891188  PMID: 19234154
Th1/Th2 Cells; Cytokine receptors; Eosinophils; Lung
20.  IL-3 is required for increases in blood basophils during nematode infection in mice and can influence IgE-dependent intra-cellular IL-4 production by basophils in vitro 
Basophils represent potential effector and immunoregulatory cells, as well as a potential source of IL-4, during the immune response elicited by infection with the nematode Nippostrongylus brasiliensis (N.b.), and in other settings. However, the factors which regulate the numbers of blood basophils in mice, or the ability of these cells to produce IL-4, are not fully understood. We found that infection of mice with the nematodes N.b. or Strongyloides venezuelensis (S.v.) induced substantial increases in the numbers of blood basophils (to as high as 18 % of circulating blood leukocytes). Experiments in IL-3−/− vs IL-3+/+ mice, and in IL-3-treated IL-3−/− mice, showed that essentially all of the increases in blood or bone marrow basophils during N.b. or S.v. infection were IL-3-dependent. Many of the blood, bone marrow or liver-derived basophils from IL-3−/− or IL-3+/+ mice expressed intra-cellular IL-4 upon stimulation with anti-IgE in vitro. However, after incubation of the cells with exogenous IgE in vitro, blood- or liver-derived basophils from IL-3+/+ mice exhibited higher levels of intra-cellular IL-4 after stimulation with anti-IgE than did basophils derived from IL-3−/− mice. Thus, IL-3 is a major regulator of the marked increases in blood basophil levels observed during infection of mice with N.b. or S.v. and also can enhance levels of intra-cellular IL-4 upon activation of basophils with anti-IgE in vitro.
PMCID: PMC2788437  PMID: 18975389
Allergy; Cytokines; Immune response; Inflammation; Mast cells; Parasites
21.  Generation of Electricity and Analysis of Microbial Communities in Wheat Straw Biomass-Powered Microbial Fuel Cells▿  
Applied and Environmental Microbiology  2009;75(11):3389-3395.
Electricity generation from wheat straw hydrolysate and the microbial ecology of electricity-producing microbial communities developed in two-chamber microbial fuel cells (MFCs) were investigated. The power density reached 123 mW/m2 with an initial hydrolysate concentration of 1,000 mg chemical oxygen demand (COD)/liter, while coulombic efficiencies ranged from 37.1 to 15.5%, corresponding to the initial hydrolysate concentrations of 250 to 2,000 mg COD/liter. The suspended bacteria found were different from the bacteria immobilized in the biofilm, and they played different roles in electricity generation from the hydrolysate. The bacteria in the biofilm were consortia with sequences similar to those of Bacteroidetes (40% of sequences), Alphaproteobacteria (20%), Bacillus (20%), Deltaproteobacteria (10%), and Gammaproteobacteria (10%), while the suspended consortia were predominately Bacillus (22.2%). The results of this study can contribute to improving understanding of and optimizing electricity generation in microbial fuel cells.
doi:10.1128/AEM.02240-08
PMCID: PMC2687294  PMID: 19376925
22.  Redox Regulation of Interleukin-4 Signaling 
Immunity  2008;29(4):551-564.
SUMMARY
The physiologic control of cytokine receptor activation is primarily mediated by reciprocal activation of receptor-associated protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Here, we show that immediately following ligand-dependent activation, IL-4 receptor induces an intracellular calcium flux via IRS-PI3K-PLC-γ pathway which, in turn, induces PKC-dependent activation of NAD(P)H oxidase (NOX)5 that generates reactive oxygen species (ROS). IL-4 also induces NOX1-mediated ROS production via IRS-PI3K-RAC1 pathway. ROS, in turn, promote IL-4 receptor activation by oxidatively inactivating PTP1B that physically associates with and deactivates IL-4 receptor. However, ROS are not required for the initiation of IL-4 receptor activation. ROS generated by activated EPO-, TNF-α- or IL-3 receptor also promote IL-4 signaling. These data reveal that inactivation of receptor-associated PTP-activity by cytokine-generated ROS is a physiologic mechanism for the amplification of cytokine receptor activation in both cis and trans, unfolding a novel means of cytokine signaling cross-talk.
doi:10.1016/j.immuni.2008.07.019
PMCID: PMC2631209  PMID: 18957266
23.  Repertoire-dependent Immunopathology 
Journal of autoimmunity  2007;29(4):257-261.
In humans, limited T-cell receptor repertoire and lymphopenia are associated with severe eosinophilic inflammatory disease. A model of lymphopenia and reduced T-cell repertoire was created; C57BL/6 Rag2−/− mice received limited (30,000) or large (2 million) numbers of CD4 T-cells. Three to five months post-transfer, mice that had received 30,000 T-cells, but not those that received 2 million, developed fulminant macrophage pneumonia with eosinophilia, Ym1 deposition. methacholine-induced airway hyperresponsiveness, eosinophilic gastritis and esophagitis. These mice had strikingly elevated serum IgE (in CD3ε−/− hosts) and donor-cells were enriched for IL-4, IL-5 and IL-13 producers. Th2 pathology and serum IgE were enhanced when transferred populations were depleted of CD25+ CD4 Tregs, but was more severe when the effector population was derived from limited as compared to the large effector population. Pretreatment of Rag2−/− mice with 300,000 CD25+ CD4 Tregs prior to effector cell transfer prevented disease while pretreatment with 30,000 did not, despite the fact that there were equal numbers of Tregs in the hosts at the time of transfer of effector cells. Limited repertoire complexity of Tregs may lead to a failure to control immunopathologic responses and limited repertoire complexity of conventional cells may be responsible for the Th2 phenotype.
doi:10.1016/j.jaut.2007.07.019
PMCID: PMC2096778  PMID: 17889507
IL-4; IL-13; IgE; alternatively activated macrophages; eosinophils
24.  A critical role for IRAK4 kinase activity in Toll-like receptor–mediated innate immunity 
The Journal of Experimental Medicine  2007;204(5):1025-1036.
IRAK4 is a member of IL-1 receptor (IL-1R)–associated kinase (IRAK) family and has been shown to play an essential role in Toll-like receptor (TLR)–mediated signaling. We recently generated IRAK4 kinase-inactive knock-in mice to examine the role of kinase activity of IRAK4 in TLR-mediated signaling pathways. The IRAK4 kinase–inactive knock-in mice were completely resistant to lipopolysaccharide (LPS)- and CpG-induced shock, due to impaired TLR-mediated induction of proinflammatory cytokines and chemokines. Although inactivation of IRAK4 kinase activity did not affect the levels of TLR/IL-1R–mediated nuclear factor κB activation, a reduction of LPS-, R848-, and IL-1–mediated mRNA stability contributed to the reduced cytokine and chemokine production in bone marrow–derived macrophages from IRAK4 kinase–inactive knock-in mice. Both TLR7- and TLR9-mediated type I interferon production was abolished in plasmacytoid dendritic cells isolated from IRAK4 knock-in mice. In addition, influenza virus–induced production of interferons in plasmacytoid DCs was also dependent on IRAK4 kinase activity. Collectively, our results indicate that IRAK4 kinase activity plays a critical role in TLR-dependent immune responses.
doi:10.1084/jem.20061825
PMCID: PMC2118590  PMID: 17470642
25.  Immune Regulation of Protease-Activated Receptor-1 Expression in Murine Small Intestine during Nippostrongylus brasiliensis Infection 
Infection with gastrointestinal nematodes exerts profound effects on both immune and physiological responses of the host. Helminth infection induces a hypercontractility of intestinal smooth muscle that is dependent on the Th2 cytokines, IL-4 and IL-13, and may contribute to worm expulsion. Protease-activated receptors (PARs) are expressed throughout the gut, and activation of PAR-1 was observed in asthma, a Th2-driven pathology. In the current study we investigated the physiologic and immunologic regulation of PAR-1 in the murine small intestine, specifically 1) the effect of PAR-1 agonists on small intestinal smooth muscle contractility, 2) the effects of Nippostrongylus brasiliensis infection on PAR-1 responses, 3) the roles of IL-13 and IL-4 in N. brasiliensis infection-induced alterations in PAR-1 responses, and 4) the STAT6 dependence of these responses. We demonstrate that PAR-1 activation induces contraction of murine intestinal smooth muscle that is enhanced during helminth infection. This hypercontractility is associated with an elevated expression of PAR-1 mRNA and protein. N. brasiliensis-induced changes in PAR-1 function and expression were seen in IL-4-deficient mice, but not in IL-13- or STAT6-deficient mice, indicating the dependence of IL-13 on the STAT6 signaling pathway independent of IL-4.
PMCID: PMC2000333  PMID: 16081830

Results 1-25 (30)