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Samuel Huber,
Nicola Gagliani, Lauren A Zenewicz,
Francis J Huber,
Lidia Bosurgi,
Bo Hu,
Matija Hedl,
Wei Zhang,
William O'Connor,
Andrew J Murphy,
David M Valenzuela,
George D Yancopoulos,
Carmen J Booth,
Judy H Cho,
Wenjun Ouyang,
Clara Abraham,
Richard A Flavell
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ABSTRACT: Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. Interleukin 22 (IL-22), a cytokine of the IL-10 superfamily, has an important role in colonic epithelial cell repair, and its levels are increased in the blood and intestine of inflammatory bowel disease patients. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, also known as IL22RA2); however, the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown. Here we describe that IL-22BP has a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells in the colon in steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent downregulation of IL-22BP, thereby increasing the ratio of IL-22/IL-22BP. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumour development if uncontrolled during the recovery phase. Thus, the IL-22-IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.
Nature 10/2012; · 36.28 Impact Factor
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ABSTRACT: Microbial penetration of the intestinal epithelial barrier triggers inflammatory responses that include induction of the bactericidal C-type lectin RegIIIγ. Systemic administration of flagellin, a bacterial protein that stimulates Toll-like receptor 5 (TLR5), induces epithelial expression of RegIIIγ and protects mice from intestinal colonization with antibiotic-resistant bacteria. Flagellin-induced RegIIIγ expression is IL-22 dependent, but how TLR signaling leads to IL-22 expression is incompletely defined. By using conditional depletion of lamina propria dendritic cell (LPDC) subsets, we demonstrated that CD103(+)CD11b(+) LPDCs, but not monocyte-derived CD103(-)CD11b(+) LPDCs, expressed high amounts of IL-23 after bacterial flagellin administration and drove IL-22-dependent RegIIIγ production. Maximal expression of IL-23 subunits IL-23p19 and IL-12p40 occurred within 60 min of exposure to flagellin. IL-23 subsequently induced a burst of IL-22 followed by sustained RegIIIγ expression. Thus, CD103(+)CD11b(+) LPDCs, in addition to promoting long-term tolerance to ingested antigens, also rapidly produce IL-23 in response to detection of flagellin in the lamina propria.
Immunity 02/2012; 36(2):276-87. · 21.64 Impact Factor
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Masahito Kamanaka,
Samuel Huber, Lauren A Zenewicz,
Nicola Gagliani,
Chozhavendan Rathinam,
William O'Connor,
Yisong Y Wan,
Susumu Nakae,
Yoichiro Iwakura,
Liming Hao,
Richard A Flavell
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ABSTRACT: The role of direct IL-10 signaling in different T cell subsets is not well understood. To address this, we generated transgenic mice expressing a dominant-negative IL-10 receptor specifically in T cells (CD4dnIL-10Rα). We found that Foxp3-depleted CD45RB(lo) (regulatory T cell [T(reg) cell]-depleted CD45RB(lo)) but not CD45RB(hi) CD4(+) T cells are controlled directly by IL-10 upon transfer into Rag1 knockout (KO) mice. Furthermore, the colitis induced by transfer of T(reg) cell-depleted CD45RB(lo) CD4(+) T cells into Rag1 KO mice was characterized by reduced Th1 and increased Th17 cytokine messenger RNA levels in the colon as compared with the colitis induced by transfer of CD45RB(hi) T cells. In contrast to the CD45RB(hi) transfer colitis model, in which IL-22 is protective, we found that T cell-derived IL-22 was pathogenic upon transfer of T(reg) cell-depleted CD45RB(lo) T cells into Rag1 KO mice. Our results highlight characteristic differences between colitis induced by naive (CD45RB(hi)) and memory/effector (T(reg) cell-depleted CD45RB(lo)) cells and different ways that IL-22 impacts inflammatory bowel disease.
Journal of Experimental Medicine 05/2011; 208(5):1027-40. · 13.85 Impact Factor
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Masahito Kamanaka,
Samuel Huber, Lauren A. Zenewicz,
Nicola Gagliani,
Chozhavendan Rathinam,
William O'Connor,
Yisong Y. Wan,
Susumu Nakae,
Yoichiro Iwakura,
Liming Hao,
Richard A. Flavell
[show abstract]
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ABSTRACT: The role of direct IL-10 signaling in different T cell subsets is not well understood. To address this, we generated transgenic
mice expressing a dominant-negative IL-10 receptor specifically in T cells (CD4dnIL-10Rα). We found that Foxp3-depleted CD45RBlo (regulatory T cell [Treg cell]–depleted CD45RBlo) but not CD45RBhi CD4+ T cells are controlled directly by IL-10 upon transfer into Rag1 knockout (KO) mice. Furthermore, the colitis induced by
transfer of Treg cell–depleted CD45RBlo CD4+ T cells into Rag1 KO mice was characterized by reduced Th1 and increased Th17 cytokine messenger RNA levels in the colon
as compared with the colitis induced by transfer of CD45RBhi T cells. In contrast to the CD45RBhi transfer colitis model, in which IL-22 is protective, we found that T cell–derived IL-22 was pathogenic upon transfer of
Treg cell–depleted CD45RBlo T cells into Rag1 KO mice. Our results highlight characteristic differences between colitis induced by naive (CD45RBhi) and memory/effector (Treg cell–depleted CD45RBlo) cells and different ways that IL-22 impacts inflammatory bowel disease.
Journal of Experimental Medicine 05/2011; 208(5):1027-1040. · 13.85 Impact Factor
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ABSTRACT: Several cell types, in particular epithelial cells, express the receptor for the cytokine IL-22 and upon its recognition produce molecules that are active both locally and systemically. Many different types of lymphocyte secrete IL-22. T(h)17 cells produce IL-22 although the optimal conditions for secretion of IL-17 or IL-22 by T(h)17 cells differ, as do the transcription factors involved. Aryl hydrocarbon receptor is required for IL-22 production by T(h)17, T(h)22 and γδ T cells. T(h)22 cells produce IL-22 in response to IL-6 and tumor necrosis factor α (TNF-α), particularly in the skin, whereas γδ T cells produce IL-22 in response to IL-23, particularly in the lung. NK cells produce IL-22 in response to IL-12 and IL-18 or IL-23. Retinoic acid-related orphan receptorγt-positive innate lymphoid cells, including lymphoid tissue inducer (LTi) and LTi-like cells express IL-22 with IL-23 again enhancing expression. IL-22 is known to be expressed in many chronic inflammatory conditions, including psoriasis and rheumatoid arthritis, and its up-regulation often correlates with disease activity. IL-22 is known to be protective in the gastrointestinal tract in inflammatory bowel disease but may mediate either harmful or helpful inflammatory responses in different models of intestinal infection. Finally, IL-22 may also play an important role in tissue repair.
International Immunology 03/2011; 23(3):159-63. · 3.41 Impact Factor
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ABSTRACT: Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) have been broadly linked to the pathogenesis of multiple autoimmune diseases. In the few short years since the discovery of T(H)17 cells, new paradigms about their prominence in chronic inflammation and human autoimmunity have emerged. Recent findings that T(H)17 cells might be capable of regulatory functions and that the associated effector molecules IL-17 and IL-22 aid in restricting tissue destruction during inflammatory episodes illuminate the complexities of IL-17 and T(H)17 biology. In this Perspective we highlight critical differences between IL-17 itself and T(H)17 cells and discuss the protective nature of IL-17 and T(H)17 cells.
Nature Immunology 06/2010; 11(6):471-6. · 26.01 Impact Factor
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ABSTRACT: The chronic autoimmune diseases include multiple complex genetic disorders. Recently, genome-wide association studies (GWAS) have identified a large number of major loci, with many associations shared between various autoimmune diseases. These associations highlight key roles for lymphocyte activation and prioritize specific cytokine pathways and mechanisms of host-microbe recognition. Despite success in identifying loci, comprehensive models of disease pathogenesis are currently lacking. Future efforts comparing association patterns between autoimmune diseases may be particularly illustrative. New genomic technologies applied to classic genetic studies involving twins, early onset cases, and phenotypic extremes may provide key insights into developmental and gene-environment interactions in autoimmunity.
Cell 03/2010; 140(6):791-7. · 32.40 Impact Factor
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ABSTRACT: Treatment of vancomycin-resistant Enterococcus (VRE) infections is limited by the paucity of effective antibiotics. Administration of broad-spectrum antibiotics promotes VRE colonization by down-regulating homeostatic innate immune defenses. Intestinal epithelial cells and Paneth cells express antimicrobial factors on direct or indirect stimulation of the Toll-like receptor (TLR)-myeloid differentiation factor 88-mediated pathway by microbe-derived molecules. Here, we demonstrate that the TLR5 agonist flagellin restores antibiotic-impaired innate immune defenses and restricts colonization with VRE. Flagellin stimulates the expression of RegIIIgamma, a secreted C-type lectin that kills gram-positive bacteria, including VRE. Systemic administration of flagellin induces RegIIIgamma expression in intestinal epithelial cells and Paneth cells along the entire length of the small intestine. Induction of RegIIIgamma requires TLR5 expression in hematopoietic cells and is dependent on interleukin 22 expression. Systemic administration of flagellin to antibiotic-treated mice dramatically reduces VRE colonization. By enhancing mucosal resistance to multidrug-resistant organisms, flagellin administration may provide a clinically useful approach to prevent infections in patients treated with broad-spectrum antibiotics.
The Journal of Infectious Diseases 02/2010; 201(4):534-43. · 6.41 Impact Factor
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ABSTRACT: Ag encounter by naive CD8 T cells initiates a developmental program consisting of cellular proliferation, changes in gene expression, and the formation of effector and memory T cells. The strength and duration of TCR signaling are known to be important parameters regulating the differentiation of naive CD8 T cells, although the molecular signals arbitrating these processes remain poorly defined. The Ras-guanyl nucleotide exchange factor RasGRP1 has been shown to transduce TCR-mediated signals critically required for the maturation of developing thymocytes. To elucidate the role of RasGRP1 in CD8 T cell differentiation, in vitro and in vivo experiments were performed with 2C TCR transgenic CD8 T cells lacking RasGRP1. In this study, we report that RasGRP1 regulates the threshold of T cell activation and Ag-induced expansion, at least in part, through the regulation of IL-2 production. Moreover, RasGRP1(-/-) 2C CD8 T cells exhibit an anergic phenotype in response to cognate Ag stimulation that is partially reversible upon the addition of exogenous IL-2. By contrast, the capacity of IL-2/IL-2R interactions to mediate Ras activation and CD8 T cell expansion and differentiation appears to be largely RasGRP1-independent. Collectively, our results demonstrate that RasGRP1 plays a selective role in T cell signaling, controlling the initiation and duration of CD8 T cell immune responses.
The Journal of Immunology 12/2009; 184(2):666-76. · 5.79 Impact Factor
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ABSTRACT: Cytokines play a major role in maintaining lymphocyte homeostasis under both steady-state and inflammatory conditions. Unregulated lymphocytes in steady-state conditions can lead to autoimmunity, whereas during inflammation they can cause excessive tissue damage. Regulatory cytokines function in combination with other environmental signals to properly modulate the function and the extent of lymphocyte activation. Many recent studies have highlighted the importance of regulatory cytokines in controlling the differentiation and function of lymphocytes under steady-state and inflammatory conditions, as well as minimizing tissue damage.
Current Opinion in Pharmacology 06/2009; 9(4):447-53. · 6.86 Impact Factor
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ABSTRACT: Differentiation of naïve T cells leads to the generation of T-cell subsets, each possessing distinct cytokine expression profiles for serving different immune functions. Through the activation of separate signaling pathways, this process results in both differentiated helper T (Th) cells, termed Th1, Th2 and Th17, and induced regulatory T cells, which suppress Th cells. These different cells are important for combating infectious diseases and cancers; however, when aberrant, they can be responsible for chronic inflammatory diseases. One such disease is inflammatory bowel disease (IBD), in which each T-cell subset can have a role in disease. New studies highlight the importance of the recently identified Th17 subset in IBD. Therapeutics targeting these aberrant Th responses are already under development and hold promise for treating IBD and other chronic inflammatory diseases.
Trends in Molecular Medicine 05/2009; 15(5):199-207. · 10.35 Impact Factor
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ABSTRACT: Inflammatory bowel disease (IBD) is a chronic inflammatory disease thought to be mediated by dysfunctional innate and/or adaptive immunity. This aberrant immune response leads to the secretion of harmful cytokines that destroy the epithelium of the gastrointestinal tract and thus cause further inflammation. Interleukin-22 (IL-22) is a T helper 17 (Th17) T cell-associated cytokine that is bifunctional in that it has both proinflammatory and protective effects on tissues depending on the inflammatory context. We show herein that IL-22 protected mice from IBD. Interestingly, not only was this protection mediated by CD4+ T cells, but IL-22-expressing natural killer (NK) cells also conferred protection. In addition, IL-22 expression was differentially regulated between NK cell subsets. Thus, both the innate and adaptive immune responses have developed protective mechanisms to counteract the damaging effects of inflammation on tissues.
Immunity 01/2009; 29(6):947-57. · 21.64 Impact Factor
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ABSTRACT: IL-22 is a Th17 T-cell-associated cytokine that is highly expressed during chronic inflammation. IL-22 receptor expression is absent on immune cells, but is instead restricted to the tissues, providing signaling directionality from the immune system to the tissues. Through Stat3 signaling, IL-22 induces a variety of proliferative, anti-apoptotic, and anti-microbial pathways. IL-22 is bi-functional with both pro-inflammatory and protective effects on tissues depending on the inflammatory context. The cytokine plays a role both in the host response against extracellular pathogens and in the inflammation associated with autoimmune diseases. Therapeutics targeting IL-22 therefore may have promise for treating various chronic inflammatory diseases.
European Journal of Immunology 12/2008; 38(12):3265-8. · 5.10 Impact Factor
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ABSTRACT: The cytokine interleukin-22 (IL-22) is primarily expressed by T helper 17 (Th17) CD4(+) T cells and is highly upregulated during chronic inflammatory diseases. IL-22 receptor expression is absent on immune cells, but is instead restricted to the tissues, providing signaling directionality from the immune system to the tissues. However, the role of IL-22 in inflammatory responses has been confounded by data suggesting both pro- and anti-inflammatory functions. Herein, we provide evidence that during inflammation, IL-22 played a protective role in preventing tissue injury. Hepatocytes from mice deficient in IL-22 were highly sensitive to the detrimental immune response associated with hepatitis. Additionally, IL-22-expressing Th17 cells provided protection during hepatitis in IL-22-deficient mice. On the other hand, interleukin-17 (IL-17), which is coexpressed with IL-22 and can induce similar cellular responses, had no observable role in liver inflammation. Our data suggest that IL-22 serves as a protective molecule to counteract the destructive nature of the immune response to limit tissue damage.
Immunity 11/2007; 27(4):647-59. · 21.64 Impact Factor
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ABSTRACT: The Gram-positive facultative intracellular bacterium Listeria monocytogenes is a model pathogen for elucidating important mechanisms of the immune response. Infection of mice with a sub-lethal dose of bacteria generates highly reproducible innate and adaptive immune responses, resulting in clearance of the bacteria and resistance to subsequent L. monocytogenes infection. Both the innate and adaptive immune systems are crucial to the recognition and elimination of this pathogen from the host.
Microbes and Infection 09/2007; 9(10):1208-15. · 3.10 Impact Factor
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ABSTRACT: The Ras-guanyl nucleotide exchange factor RasGRP1 is an important link between TCR-mediated signaling and the activation of Ras and its downstream effectors. RasGRP1 is especially critical for the survival and differentiation of developing thymocytes whereas negative selection of thymocytes bearing an autoreactive TCR appears to be RasGRP1 independent. Despite apparently normal central tolerance, RasGRP1(-/-) mice spontaneously acquire an acutely activated and proliferating CD4 T cell population that exhibits characteristics of T cell exhaustion, including strong expression of programmed cell death-1. To elucidate the basis for RasGRP1(-/-) CD4 T cell immune activation, we initiated a series of adoptive transfer experiments. Remarkably, the copious amounts of cytokines and self-Ags present in hosts made lymphopenic through irradiation failed to induce the majority of RasGRP1(-/-) CD4 T cells to enter cell cycle. However, their infusion into either congenitally T cell- or T/B cell-deficient recipients resulted in robust proliferation and L-selectin down-regulation. These findings imply that the activation and proliferation of RasGRP1(-/-) CD4 T cells may be dependent on their residence in a chronically immunocompromised environment. Accordingly, bacterial and viral challenge experiments revealed that RasGRP1(-/-) mice possess a weakened immune system, exhibiting a T cell-autonomous defect in generating pathogen-specific T cells and delayed pathogen clearance. Collectively, our study suggests that chronic T cell immunodeficiency in RasGRP1(-/-) mice may be responsible for CD4 T cell activation, proliferation, and exhaustion.
The Journal of Immunology 09/2007; 179(4):2143-52. · 5.79 Impact Factor
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ABSTRACT: Listeria monocytogenes has long served as a model pathogen for elucidating many functions of the immune response. Both the innate and adaptive immune
systems are crucial to the recognition and elimination of this pathogen from the host. However, although L. monocytogenes infection induces robust immune responses, the bacterium has evolved mechanisms to evade and modulate the immune response.
Its intracellular niche allows it to evade several aspects of the innate and adaptive immune systems. Expression of different
virulence factors during infection leads to modulation of other arms of the immune response. In this chapter, we focus on
the specific mechanisms L. monocytogenes has evolved to evade and modulate the host immune response
06/2007: pages 251-263;
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ABSTRACT: Two virulence factors of Listeria monocytogenes, listeriolysin O (LLO) and phosphatidylinositol-specific phospholipase C (PI-PLC), mediate escape of this pathogen from the phagocytic vacuole of macrophages, thereby allowing the bacterium access to the host cell cytosol for growth and spread to neighboring cells. We characterized their orthologs from Bacillus anthracis by expressing them in L. monocytogenes and characterizing their contribution to bacterial intracellular growth and cell-to-cell spread. We generated a series of L. monocytogenes strains expressing B. anthracis anthrolysin O (ALO) and PI-PLC in place of LLO and L. monocytogenes PI-PLC, respectively. We found that ALO was active at both acidic and neutral pH and could functionally replace LLO in mediating escape from a primary vacuole; however, ALO exerted a toxic effect on the host cell by damaging the plasma membrane. B. anthracis PI-PLC, unlike the L. monocytogenes ortholog, had high activity on glycosylphosphatidylinositol-anchored proteins. L. monocytogenes expressing B. anthracis PI-PLC showed significantly decreased efficiencies of escape from a phagosome and in cell-to-cell spread. We further compared the level of cytotoxicity to host cells by using mutant strains expressing ALO in combination either with L. monocytogenes PI-PLC or with B. anthracis PI-PLC. The results demonstrated that the mutant strain expressing the combination of ALO and B. anthracis PI-PLC caused less damage to host cells than the strain expressing ALO and L. monocytogenes PI-PLC. The present study indicates that LLO and L. monocytogenes PI-PLC has adapted for L. monocytogenes intracellular growth and virulence and suggests that ALO and B. anthracis PI-PLC may have a role in B. anthracis pathogenesis.
Infection and Immunity 11/2005; 73(10):6639-46. · 4.16 Impact Factor
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ABSTRACT: Listeria monocytogenes phosphatidylinositol-specific phospholipase C (PI-PLC) plays a critical role in escape of this human pathogen from host cell vacuoles. Unlike classical bacterial PI-PLCs, the L. monocytogenes enzyme has very weak activity on glycosylphosphatidylinositol (GPI)-anchored proteins. Previous crystal structure analysis has revealed that a small beta-strand (Vb) is present in Bacillus cereus PI-PLC and is absent in the enzyme from L. monocytogenes. This Vb beta-strand in B. cereus PI-PLC forms contacts with the glycan linker of GPI anchors, which presumably increases its activity on GPI-anchored proteins. In this study, we show that, of all known bacterial PI-PLCs, those from listeriae are the only ones that lack the beta-strand. Expression by L. monocytogenes of B. cereus PI-PLC, which has strong activity on GPI-anchored proteins, inhibited bacterial escape from a vacuole and cell-to-cell spread, resulting in greatly reduced virulence in mice. Deletion of the Vb beta-strand from B. cereus PI-PLC abolished its ability to cleave GPI-anchored proteins, decreased its inhibitory effects, and increased its virulence in mice. These results strongly suggest that L. monocytogenes PI-PLC has evolved as an important determinant of L. monocytogenes pathogenesis by absence of the Vb beta-strand, thus leading to greatly reduced activity on GPI-anchored proteins.
Proceedings of the National Academy of Sciences 10/2005; 102(36):12927-31. · 9.68 Impact Factor
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ABSTRACT: The human gut is host to hundreds of different species of commensal bacteria that live in peaceful partnership with the host immune system. These commensal bacteria are far from neutral bystanders as they are intimately involved in the development of the immune system. Reporting in this issue of Cell, Kasper and colleagues (Mazmanian et al., 2005) reveal that a bacterial polysaccharide, PSA, produced by the commensal bacterium Bacteroides fragilis directs development of the immune system of the mouse host.
Cell 08/2005; 122(1):2-4. · 32.40 Impact Factor
