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  • Enhanced protection conferred by mucosal BCG vaccination associates with presence of antigen-specific lung tissue-resident PD-1+ KLRG1− CD4+ T cells
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-11-16
    N. C. Bull, E. Stylianou, D. A. Kaveh, N. Pinpathomrat, J. Pasricha, R. Harrington-Kandt, M. C. Garcia-Pelayo, P. J. Hogarth, H. McShane

    BCG, the only vaccine licensed against tuberculosis, demonstrates variable efficacy in humans. Recent preclinical studies highlight the potential for mucosal BCG vaccination to improve protection. Lung tissue-resident memory T cells reside within the parenchyma, potentially playing an important role in protective immunity to tuberculosis. We hypothesised that mucosal BCG vaccination may enhance generation of lung tissue-resident T cells, affording improved protection against Mycobacterium tuberculosis. In a mouse model, mucosal intranasal (IN) BCG vaccination conferred superior protection in the lungs compared to the systemic intradermal (ID) route. Intravascular staining allowed discrimination of lung tissue-resident CD4+ T cells from those in the lung vasculature, revealing that mucosal vaccination resulted in an increased frequency of antigen-specific tissue-resident CD4+ T cells compared to systemic vaccination. Tissue-resident CD4+ T cells induced by mucosal BCG displayed enhanced proliferative capacity compared to lung vascular and splenic CD4+ T cells. Only mucosal BCG induced antigen-specific tissue-resident T cells expressing a PD-1+ KLRG1− cell-surface phenotype. These cells constitute a BCG-induced population which may be responsible for the enhanced protection observed with IN vaccination. We demonstrate that mucosal BCG vaccination significantly improves protection over systemic BCG and this correlates with a novel population of BCG-induced lung tissue-resident CD4+ T cells.

    更新日期:2018-11-16
  • Selective expression of constitutively activated STAT6 in intestinal epithelial cells promotes differentiation of secretory cells and protection against helminths
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-11-16
    Christoph Schubart, Branislav Krljanac, Manuel Otte, Cornelia Symowski, Eva Martini, Claudia Günther, Christoph Becker, Christoph Daniel, David Voehringer

    Intestinal epithelial cells (IECs) constitute an important barrier between host and pathogen. Immune mechanisms that provide protection against gastrointestinal helminths often require IL-4Rα-induced activation of STAT6-regulated genes in IECs. However, it is not known whether STAT6 activation in IECs enhances protective immunity against helminths. Furthermore, the regulation of proliferation and differentiation processes of the intestinal epithelium by IEC-intrinsic STAT6 signaling remains unclear. To address these questions, we generated mice with specific expression of a constitutively active version of STAT6 in IECs. These VillinCre_STAT6vt mice show accumulation of secretory IECs, increased proliferation of IECs and lengthening of the small intestine. They rapidly expelled Nippostrongylus brasiliensis worms even in the absence of T cells. Furthermore, primary infection with Heligmosomoides polygyrus resulted in larval trapping in the submucosa and the fecundity of adult worms was severely impaired. Our results reveal an important IEC-intrinsic role of STAT6-regulated genes for intestinal homeostasis and protective immunity against helminths.

    更新日期:2018-11-16
  • Intestinal helminth infection promotes IL-5- and CD4+ T cell-dependent immunity in the lung against migrating parasites
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-11-06
    Kara J. Filbey, Mali Camberis, Jodie Chandler, Rufus Turner, Anthony J. Kettle, Ramon M. Eichenberger, Paul Giacomin, Graham Le Gros

    The ability of helminths to manipulate the immune system of their hosts to ensure their own survival is often credited with affecting responses to other pathogens. We undertook co-infection experiments in mice to determine how infection with the intestinal helminth Heligmosomoides polygyrus affected the parasitological, immunological and physiological outcomes of a primary infection with a distinct species of helminth; the lung migratory parasite Nippostrongylus brasiliensis. We found that migrating N. brasiliensis larvae were killed in the lungs of H. polygyrus-infected mice by a process involving IL-33-activated CD4+ T cells that released IL-5 and recruited activated eosinophils. The lung pathology normally associated with N. brasiliensis larval migration was also reduced. Importantly, lung immunity remained intact in mice cleared of prior H. polygyrus infection and also occurred during infection with another entirely enteric helminth, Trichuris muris. This study identifies a cross-mucosal immune mechanism by which intestinal helminths may protect their hosts against co-infection by a different parasite at a distal site, via circulation of activated CD4+ T cells that can be triggered to release effector cytokines and mount inflammatory responses by tissue damage-associated alarmins, such as IL-33.

    更新日期:2018-11-06
  • Correction: E. coli Nissle 1917 is a safe mucosal delivery vector for a birch-grass pollen chimera to prevent allergic poly-sensitization
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-11-01
    P. J. Sarate, S. Heinl, S. Poiret, M. Drinić, C. Zwicker, I. Schabussova, C. Daniel, U. Wiedermann

    Correction: E. coli Nissle 1917 is a safe mucosal delivery vector for a birch-grass pollen chimera to prevent allergic poly-sensitization Correction: E. coli Nissle 1917 is a safe mucosal delivery vector for a birch-grass pollen chimera to prevent allergic poly-sensitization, Published online: 01 November 2018; doi:10.1038/s41385-018-0103-7 Correction: E. coli Nissle 1917 is a safe mucosal delivery vector for a birch-grass pollen chimera to prevent allergic poly-sensitization

    更新日期:2018-11-02
  • Virtual memory CD8 T cells expanded by helminth infection confer broad protection against bacterial infection
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-25
    J. S. Lin, K. Mohrs, F. M. Szaba, L. W. Kummer, E. A. Leadbetter, M. Mohrs

    Epidemiological data and animal studies suggest that helminth infection exerts potent immunomodulatory effects that dampen host immunity against unrelated pathogens. Despite this notion, we unexpectedly discovered that prior helminth infection resulted in enhanced protection against subsequent systemic and enteric bacterial infection. A population of virtual memory CD8 T (CD8 TVM) cells underwent marked expansion upon infection with the helminth Heligmosomoides polygurus by an IL-4-regulated, antigen-independent mechanism. CD8 TVM cells disseminated to secondary lymphoid organs and established a major population of the systemic CD8 T cell pool. IL-4 production elicited by protein immunization or selective activation of natural killer T cells also results in the expansion of CD8 TVM cells. Notably, CD8 TVM cells expanded by helminth infection are sufficient to transfer innate non-cognate protection against bacteria to naïve animals. This innate non-cognate “collateral protection” mediated by CD8 TVM might provide parasitized animals an advantage against subsequent unrelated infections, and represents a potential novel strategy for vaccination.

    更新日期:2018-10-26
  • Entamoeba histolytica-induced IL-1β secretion is dependent on caspase-4 and gasdermin D
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-25
    Jeanie Quach, France Moreau, Christina Sandall, Kris Chadee

    During invasion, Entamoeba histolytica (Eh) encounter macrophages and activate them to elicit tissue damaging pro-inflammatory responses. When Eh binds macrophages via the Gal-lectin, surface EhCP-A5 RGD sequence ligates α5β1 integrin to activate caspase-1 in a complex known as the NLRP3 inflammasome. In this study, we investigated Eh requirements underlying macrophage caspase-4 and -1 activation and the role caspase-4 and gasdermin D (GSDMD) play in augmenting pro-inflammatory cytokine responses. Caspase-4 activation was similar to caspase-1 requiring live Eh attachment via the Gal-lectin and EhCP-A5. However, unlike caspase-1, caspase-4 activation was independent of ASC and NLRP3. Using CRISPR/Cas9 gene editing of caspase-4 and -1 and GSDMD, we determined that caspase-1 and bioactive IL-1β release was highly dependent on caspase-4 activation and cleavage of GSDMD in response to Eh. Formaldehyde cross-linking to stabilize protein–protein interactions in transfected COS-7 cells stimulated with Eh revealed that caspase-4 specifically interacted with caspase-1 in a protein complex that enhanced the cleavage of caspase-1 CARD domains to augment IL-1β release. Activated caspase-4 and -1 cleaved GSDMD liberating the N-terminal p30 pore-forming fragment that caused the secretion of IL-1β. These findings reveal a novel role for caspase-4 as a sensor molecule to amplify pro-inflammatory responses when macrophage encounters Eh.

    更新日期:2018-10-25
  • Different flavors of IL-21 in regulation of intestinal IgA to commensals
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-25
    Yingzi Cong, Yanqing Li

    Different flavors of IL-21 in regulation of intestinal IgA to commensals Different flavors of IL-21 in regulation of intestinal IgA to commensals, Published online: 25 October 2018; doi:10.1038/s41385-018-0099-z Different flavors of IL-21 in regulation of intestinal IgA to commensals

    更新日期:2018-10-25
  • T-bet controls intestinal mucosa immune responses via repression of type 2 innate lymphoid cell function
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-24
    N. Garrido-Mesa, J-H. Schroeder, E. Stolarczyk, A. L. Gallagher, J. W. Lo, C. Bailey, L. Campbell, V. Sexl, T. T. MacDonald, J. K. Howard, R. K. Grencis, N. Powell, G. M. Lord

    Innate lymphoid cells (ILCs) play an important role in regulating immune responses at mucosal surfaces. The transcription factor T-bet is crucial for the function of ILC1s and NCR+ ILC3s and constitutive deletion of T-bet prevents the development of these subsets. Lack of T-bet in the absence of an adaptive immune system causes microbiota-dependent colitis to occur due to aberrant ILC3 responses. Thus, T-bet expression in the innate immune system has been considered to dampen pathogenic immune responses. Here, we show that T-bet plays an unexpected role in negatively regulating innate type 2 responses, in the context of an otherwise intact immune system. Selective loss of T-bet in ILCs leads to the expansion and increased activity of ILC2s, which has a functionally important impact on mucosal immunity, including enhanced protection from Trichinella spiralis infection and inflammatory colitis. Mechanistically, we show that T-bet controls the intestinal ILC pool through regulation of IL-7 receptor signalling. These data demonstrate that T-bet expression in ILCs acts as the key transcriptional checkpoint in regulating pathogenic vs. protective mucosal immune responses, which has significant implications for the understanding of the pathogenesis of inflammatory bowel diseases and intestinal infections.

    更新日期:2018-10-24
  • The emergence of pathogenic TNF/iNOS producing dendritic cells (Tip-DCs) in a malaria model of acute respiratory distress syndrome (ARDS) is dependent on CCR4
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-18
    Bruno Galvão-Filho, Júlia Teixeira de Castro, Maria Marta Figueiredo, Claudio Gonçalves Rosmaninho, Lis Ribeiro do Valle Antonelli, Ricardo Tostes Gazzinelli

    Malaria-associated acute respiratory distress syndrome (MA-ARDS) and acute lung injury (ALI) are complications that cause lung damage and often leads to death. The MA-ARDS/ALI is associated with a Type 1 inflammatory response mediated by T lymphocytes and IFN-γ. Here, we used the Plasmodium berghei NK65 (PbN)-induced MA-ALI/ARDS model that resembles human disease and confirmed that lung CD4+ and CD8+ T cells predominantly expressed Tbet and IFN-γ. Surprisingly, we found that development of MA-ALI/ARDS was dependent on functional CCR4, known to mediate the recruitment of Th2 lymphocytes and regulatory T cells. However, in this Type 1 inflammation-ARDS model, CCR4 was not involved in the recruitment of T lymphocytes, but was required for the emergence of TNF-α/iNOS producing dendritic cells (Tip-DCs) in the lungs. In contrast, recruitment of Tip-DCs and development of MA-ALI/ARDS were not altered in CCR2−/− mice. Importantly, we showed that NOS2−/− mice are resistant to PbN-induced lung damage, indicating that reactive nitrogen species produced by Tip-DCs play an essential role in inducing MA-ARDS/ALI. Lastly, our experiments suggest that production of IFN-γ primarily by CD8+ T cells is required for inducing Tip-DCs differentiation in the lungs and the development of MA-ALI/ARDS model.

    更新日期:2018-10-18
  • Macrophages promote epithelial proliferation following infectious and non-infectious lung injury through a Trefoil factor 2-dependent mechanism
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-18
    Li-Yin Hung, Debasish Sen, Taylor K. Oniskey, Jeremey Katzen, Noam A. Cohen, Andrew E. Vaughan, Wildaliz Nieves, Anatoly Urisman, Michael F. Beers, Matthew F. Krummel, De’Broski R. Herbert

    Coordinated efforts between macrophages and epithelia are considered essential for wound healing, but the macrophage-derived molecules responsible for repair are poorly defined. This work demonstrates that lung macrophages rely upon Trefoil factor 2 to promote epithelial proliferation following damage caused by sterile wounding, Nippostrongylus brasiliensis or Bleomycin sulfate. Unexpectedly, the presence of T, B, or ILC populations was not essential for macrophage-driven repair. Instead, conditional deletion of TFF2 in myeloid-restricted CD11cCre TFF2 flox mice exacerbated lung pathology and reduced the proliferative expansion of CD45− EpCAM+ pro-SPC+ alveolar type 2 cells. TFF2 deficient macrophages had reduced expression of the Wnt genes Wnt4 and Wnt16 and reconstitution of hookworm-infected CD11cCre TFF2flox mice with rWnt4 and rWnt16 restored the proliferative defect in lung epithelia post-injury. These data reveal a previously unrecognized mechanism wherein lung myeloid phagocytes utilize a TFF2/Wnt axis as a mechanism that drives epithelial proliferation following lung injury.

    更新日期:2018-10-18
  • Immature lung TNFR2− conventional DC 2 subpopulation activates moDCs to promote cyclic di-GMP mucosal adjuvant responses in vivo
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-16
    Samira Mansouri, Seema Patel, Divya S. Katikaneni, Steven M. Blaauboer, Wei Wang, Stefan Schattgen, Katherine Fitzgerald, Lei Jin

    Cyclic dinucleotides (CDNs), including cyclic di-GMP (CDG), are promising vaccine adjuvants in preclinical/clinical trials. The in vivo mechanisms of CDNs are not clear. Here we investigated the roles of lung DC subsets in promoting CDG mucosal adjuvant responses in vivo. Using genetically modified mice and adoptive cell transfer, we identified lung conventional DC 2 (cDC2) as the central player in CDG mucosal responses. We further identified two functionally distinct lung cDC2 subpopulations: TNFR2+pRelB+ and TNFR2−pRelB− cDC2. The TNFR2+ cDC2 were mature and migratory upon intranasal CDG administration while the TNFR2− cDC2 were activated but not mature. Adoptive cell transfer showed that TNFR2− cDC2 mediate the antibody responses of CDG, while the TNFR2+ cDC2 generate Th1/17 responses. Mechanistically, immature TNFR2− cDC2 activate monocyte-derived DCs (moDCs), which do not take up intranasally administered CDG. moDCs promote CDG-induced generation of T follicular helper- and germinal center B cells in the lungs. Our data revealed a previously undescribed in vivo mode of DCs action, whereby an immature lung TNFR2− cDC2 subpopulation directs the non-migratory moDCs to generate CDG mucosal responses in the lung.

    更新日期:2018-10-17
  • Novel role of gastric releasing peptide-mediated signaling in the host response to influenza infection
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-16
    Kari Ann Shirey, Mary E. Sunday, Wendy Lai, Mira C. Patel, Jorge C. G. Blanco, Frank Cuttitta, Stefanie N. Vogel

    Gastrin-releasing peptide (GRP) is an evolutionarily well-conserved neuropeptide that was originally recognized for its ability to mediate gastric acid secretion in the gut. More recently, however, GRP has been implicated in pulmonary lung inflammatory diseases including bronchopulmonary dysplasia, chronic obstructive pulmonary disease, emphysema, and others. Antagonizing GRP or its receptor mitigated lethality associated with the onset of viral pneumonia in a well-characterized mouse model of influenza. In mice treated therapeutically with the small-molecule GRP inhibitor, NSC77427, increased survival was accompanied by decreased numbers of GRP-producing pulmonary neuroendocrine cells, improved lung histopathology, and suppressed cytokine gene expression. In addition, in vitro studies in macrophages indicate that GRP synergizes with the prototype TLR4 agonist, lipopolysaccharide, to induce cytokine gene expression. Thus, these findings reveal that GRP is a previously unidentified mediator of influenza-induced inflammatory disease that is a potentially novel target for therapeutic intervention.

    更新日期:2018-10-17
  • A selective window after the food-intake period favors tolerance induction in mesenteric lymph nodes
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-16
    Bibiana E. Barrios, Lisa Maccio-Maretto, F. Nicolás Nazar, Silvia G. Correa

    Biological rhythms are periodic oscillations that occur in the physiology of the organism and the cells. The rhythms of the immune system are strictly regulated and the circadian alteration seems to have serious consequences. Even so, it is not clear how the immune cells of the intestinal mucosa synchronize with the external environment. Besides, little is known about the way in which biological rhythms affect the critical functions of intestinal immunity, such as oral tolerance. We studied fluctuations in the relevant parameters of intestinal immunity at four different times throughout the day. By using multivariate statistical tools, we found that these oscillations represent at least three different time frames with different conditions for tolerance induction that are altered in Per2ko mice lacking one of the clock genes. Our results allowed us to characterize a window in the final stage of the dark phase that promotes the induction of specific regulatory populations and favors its location in the lamina propria. We show here that, at the end of the intake, the entry of luminal antigens, soluble factors, and leukocyte populations converge in the mesenteric lymph nodes (MLN) and display the greatest potential of the tolerogenic machinery.

    更新日期:2018-10-17
  • Subcellular antigen localization in commensal E. coli is critical for T cell activation and induction of specific tolerance
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-16
    Eveline Bennek, Ana D. Mandić, Julien Verdier, Silvia Roubrocks, Oliver Pabst, Niels Van Best, Inga Benz, Thomas Kufer, Christian Trautwein, Gernot Sellge

    Oral tolerance to soluble antigens is critically important for the maintenance of immunological homeostasis in the gut. The mechanisms of tolerance induction to antigens of the gut microbiota are still less well understood. Here, we investigate whether the subcellular localization of antigens within non-pathogenic E. coli has a role for its ability to induce antigen-specific tolerance. E. coli that express an ovalbumin (OVA) peptide in the cytoplasm, at the outer membrane or as secreted protein were generated. Intestinal colonization of mice with non-pathogenic E. coli expressing OVA at the membrane induced the expansion of antigen-specific Foxp3+ Tregs and mediated systemic immune tolerance. In contrast, cytoplasmic OVA was ignored by antigen-specific CD4+ T cells and failed to induce tolerance. In vitro experiments revealed that surface-displayed OVA of viable E. coli was about two times of magnitude more efficient to activate antigen-specific CD4+ T cells than soluble antigens, surface-displayed antigens of heat-killed E. coli or cytoplasmic antigen of viable or heat-killed E. coli. This effect was independent of the antigen uptake efficiency in dendritic cells. In summary, our results show that subcellular antigen localization in viable E. coli strongly influences antigen-specific CD4+ cell expansion and tolerance induction upon intestinal colonization.

    更新日期:2018-10-16
  • miR-106a deficiency attenuates inflammation in murine IBD models
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-16
    Megan R. Sanctuary, Rick H. Huang, Ashleigh A. Jones, Marisa E. Luck, Carol M. Aherne, Paul Jedlicka, Edwin F. de Zoeten, Colm B. Collins

    Pro-inflammatory cytokine TNFα antagonizes regulatory T cell (Treg) suppressive function with a measurable reduction of IL-10 protein secretion. Tregs are critical to suppress excessive immune activation, particularly within the intestine where high antigenic loads elicit chronic subclinical immune activation. Employing a TNFα-driven murine inflammatory bowel disease (IBD) model (TNFΔARE/+), which mirrors the Treg expansion and transmural ileitis seen in Crohn’s disease, we demonstrate that the TNFα-mediated loss of Treg suppressive function coincides with induction of a specific miRNA, miR-106a in both humans and mice, via NFκB promoter binding to suppress post-transcriptional regulation of IL-10 release. Elevation of miR-106a and impaired Treg function in this model recapitulate clinical data from IBD patients. MiR-106a deficiency promotes Treg induction, suppressive function and IL-10 production in vitro. MiR-106a knockout attenuated chronic murine ileitis, whereas T cell restricted deficiency of miR-106a attenuated adoptive transfer colitis. In both models, attenuated inflammation coincided with suppression of both Th1 and Th17 cell subset expansion within the intestinal lamina propria. Collectively, our data demonstrate impaired Treg suppressive function in a murine IBD model consistent with human disease and support the potential for inhibition of miR-106a as a future therapeutic approach to treat chronic inflammatory conditions including IBD.

    更新日期:2018-10-16
  • Characterization of CD28null T cells in idiopathic pulmonary fibrosis
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-12
    David M. Habiel, Milena S. Espindola, Chris Kitson, Anthony V. Azzara, Ana Lucia Coelho, Barry Stripp, Cory M. Hogaboam

    Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease, with unknown etiopathogenesis and suboptimal therapeutic options. Previous reports have shown that increased T-cell numbers and CD28null phenotype is predictive of prognosis in IPF, suggesting that these cells might have a role in this disease. Flow cytometric analysis of explanted lung cellular suspensions showed a significant increase in CD8+ CD28null T cells in IPF relative to normal lung explants. Transcriptomic analysis of CD3+ T cells isolated from IPF lung explants revealed a loss of CD28-transcript expression and elevation of pro-inflammatory cytokine expression in IPF relative to normal T cells. IPF lung explant-derived T cells (enriched with CD28null T cells), but not normal donor lung CD28+ T cells induced dexamethasone-resistant lung remodeling in humanized NSG mice. Finally, CD28null T cells expressed similar CTLA4 and significantly higher levels of PD-1 proteins relative to CD28+ T cells and blockade of either proteins in humanized NSG mice, using anti-CTLA4, or anti-PD1, mAb treatment-accelerated lung fibrosis. Together, these results demonstrate that IPF CD28null T cells may promote lung fibrosis but the immune checkpoint proteins, CTLA-4 and PD-1, appears to limit this effect.

    更新日期:2018-10-12
  • CLA-supplemented diet accelerates experimental colorectal cancer by inducing TGF-β-producing macrophages and T cells
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-02
    T. G. Moreira, L. S. Horta, A. C. Gomes-Santos, R. P. Oliveira, N. M. G. P. Queiroz, D. Mangani, B Daniel, A. T. Vieira, S. Liu, A. M. Rodrigues, D. A. Gomes, G. Gabriely, E. Ferreira, H. L. Weiner, R. M. Rezende, L. Nagy, A. M. C. Faria

    Conjugated linoleic acid (CLA) has been shown to activate the nuclear receptor PPAR-γ and modulate metabolic and immune functions. Despite the worldwide use of CLA dietary supplementation, strong scientific evidence for its proposed beneficial actions are missing. We found that CLA-supplemented diet reduced mucosal damage and inflammatory infiltrate in the dextran sodium sulfate (DSS)-induced colitis model. Conditional deletion of PPAR-γ in macrophages from mice supplemented with CLA diet resulted in loss of this protective effect of CLA, suggesting a PPAR-γ-dependent mechanism mediated by macrophages. However, CLA supplementation significantly worsened colorectal tumor formation induced by azoxymethane and DSS by inducing macrophage and T-cell-producing TGF-β via PPAR-γ activation. Accordingly, either macrophage-specific deletion of PPAR-γ or in vivo neutralization of latency-associated peptide (LAP, a membrane-bound TGF-β)-expressing cells abrogated the protumorigenic effect of CLA. Thus, the anti-inflammatory properties of CLA are associated with prevention of colitis but also with development of colorectal cancer.

    更新日期:2018-10-03
  • NOX1-derived ROS drive the expression of Lipocalin-2 in colonic epithelial cells in inflammatory conditions
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-02
    Nesrine Makhezer, Marwa Ben Khemis, Dan Liu, Yamina Khichane, Viviana Marzaioli, Asma Tlili, Marjan Mojallali, Coralie Pintard, Philippe Letteron, Margarita Hurtado-Nedelec, Jamel El-Benna, Jean-Claude Marie, Aurélie Sannier, Anne-Laure Pelletier, Pham My-Chan Dang

    Inflammatory bowel disease (IBD) is characterized by severe and recurrent inflammation of the gastrointestinal tract, associated with altered patterns of cytokine synthesis, excessive reactive oxygen species (ROS) production, and high levels of the innate immune protein, lipocalin-2 (LCN-2), in the mucosa. The major source of ROS in intestinal epithelial cells is the NADPH oxidase NOX1, which consists of the transmembrane proteins, NOX1 and p22PHOX, and the cytosolic proteins, NOXO1, NOXA1, and Rac1. Here, we investigated whether NOX1 activation and ROS production induced by key inflammatory cytokines in IBD causally affects LCN-2 production in colonic epithelial cells. We found that the combination of TNFα and IL-17 induced a dramatic upregulation of NOXO1 expression that was dependent on the activation of p38MAPK and JNK1/2, and resulted into an increase of NOX1 activity and ROS production. NOX1-derived ROS drive the expression of LCN-2 by controlling the expression of IκBζ, a master inducer of LCN-2. Furthermore, LCN-2 production and colon damage were decreased in NOX1-deficient mice during TNBS-induced colitis. Finally, analyses of biopsies from patients with Crohn’s disease showed increased JNK1/2 activation, and NOXO1 and LCN-2 expression. Therefore, NOX1 might play a key role in mucosal immunity and inflammation by controlling LCN-2 expression.

    更新日期:2018-10-03
  • Resolvin D1 treatment on goblet cell mucin and immune responses in the chronic allergic eye disease (AED) model
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-02
    Daniel R. Saban, Robin R. Hodges, Rose Mathew, Nancy J. Reyes, Chen Yu, Rebecca Kaye, William Swift, Nora Botten, Charles N. Serhan, Darlene A. Dartt

    Severe, chronic eye allergy is an understudied, vision-threatening condition. Treatments remain limited. We used a mouse model of severe allergic eye disease (AED) to determine whether topical application of the pro-resolution mediator Resolvin D1 (RvD1) terminates the response. AED was induced by injection of ovalbumin (OVA) followed by topical challenge of OVA daily. RvD1 was applied topically prior to OVA. Clinical symptoms were scored. Eye washes were assayed for MUC5AC. After 7 days, eyes were removed and the number of goblet cells, T helper cell responses and presence of immune cells in draining lymph nodes and conjunctiva determined. Topical RvD1 treatment significantly reduced symptoms of AED. RvD1 did not alter the systemic type 2 immune response in the lymph nodes. AED increased the total amount of goblet cell mucin secretion, but not the number of goblet cells. RvD1 prevented this increase, but did not alter goblet cell number. Absolute numbers of CD4 + T cells, total CD11b + myeloid cells, eosinophils, neutrophils, and monocytes, but not macrophages increased in AED versus RvD1-treated mice. We conclude that topical application of RvD1 reduced the ocular allergic response by local actions in conjunctival immune response and a decrease in goblet cell mucin secretion.

    更新日期:2018-10-03
  • Succinate receptor mediates intestinal inflammation and fibrosis
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-02
    Dulce C. Macias-Ceja, Dolores Ortiz-Masiá, Pedro Salvador, Laura Gisbert-Ferrándiz, Carlos Hernández, Martin Hausmann, Gerhard Rogler, Juan V. Esplugues, Joaquín Hinojosa, Rafael Alós, Francisco Navarro, Jesus Cosin-Roger, Sara Calatayud, María D. Barrachina

    Succinate, an intermediate of the tricarboxylic acid cycle, is accumulated in inflamed areas and its signaling through succinate receptor (SUCNR1) regulates immune function. We analyze SUCNR1 expression in the intestine of Crohn's disease patients and its role in murine intestinal inflammation and fibrosis. We show that both serum and intestinal succinate levels and SUCNR1 expression in intestinal surgical resections were higher in CD patients than in controls. SUCNR1 co-localized with CD86, CD206, and α-SMA+ cells in human intestine and we found a positive and significant correlation between SUCNR1 and α-SMA expression. In human isolated fibroblasts from CD patients SUCNR1 expression was higher than in those from controls and treatment with succinate increased SUCNR1 expression, fibrotic markers and inflammatory cytokines through SUCNR1. This receptor modulated the expression of pro-inflammatory cytokines in resting murine macrophages, macrophage polarization and fibroblast activation and Sucnr1−/− mice were protected against both acute TNBS-colitis and intestinal fibrosis induced by the heterotopic transplant of colonic tissue. We demonstrate increased succinate levels in serum and SUCNR1 expression in intestinal tissue of CD patients and show a role for SUCNR1 in murine intestinal inflammation and fibrosis.

    更新日期:2018-10-03
  • A dendritic cell-based systemic vaccine induces long-lived lung-resident memory Th17 cells and ameliorates pulmonary mycosis
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-02
    Keigo Ueno, Makoto Urai, Sota Sadamoto, Minoru Shinozaki, Shogo Takatsuka, Masahiro Abe, Yoshiko Otani, Nao Yanagihara, Kiminori Shimizu, Yoichiro Iwakura, Kazutoshi Shibuya, Yoshitsugu Miyazaki, Yuki Kinjo

    Tissue-resident memory T cells (TRMs) are a novel nonvascular memory T cell subset. Although CD8+ TRMs are well-characterized, CD4+ TRMs—especially lung-resident memory Th17 cells—are still being defined. In this study, we characterized lung-resident memory Th17 cells (lung TRM17) and their role in protection against the highly virulent fungus Cryptococcus gattii. We found that intravenously transferred DCs preferentially migrated to lungs and attracted recipient DCs and led to the induction of long-lived Th17 cells expressing characteristic markers. This population could be clearly discriminated from circulating T cells by intravascular staining and was not depleted by the immunosuppressive agent FTY720. The C. gattii antigen re-stimulation assay revealed that vaccine-induced lung Th17 cells produced IL-17A but not IFNγ. The DC vaccine significantly increased IL-17A production and suppressed fungal burden in the lungs and improved the survival of mice infected with C. gattii. This protective effect was significantly reduced in the IL-17A knockout (KO) mice, but not in the FTY720-treated mice. The protective effect also coincided with the activation of neutrophils and multinucleated giant cells, and these inflammatory responses were suppressed in the vaccinated IL-17A KO mice. Overall, these data demonstrated that the systemic DC vaccine induced lung TRM17, which played a substantial role in anti-fungal immunity.

    更新日期:2018-10-03
  • Non-toxigenic Bacteroides fragilis (NTBF) administration reduces bacteria-driven chronic colitis and tumor development independent of polysaccharide A
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-02
    June L. Chan, Shaoguang Wu, Abby L. Geis, Gabrielle V. Chan, Talles A. M. Gomes, Sarah E. Beck, Xinqun Wu, Hongni Fan, Ada J. Tam, Liam Chung, Hua Ding, Hao Wang, Drew M. Pardoll, Franck Housseau, Cynthia L. Sears

    Polysaccharide A (PSA), an immunogenic capsular component of non-toxigenic Bacteroides fragilis (NTBF) strain NCTC 9343, is reported to promote mucosal immune development and suppress colitis. Contrastingly, enterotoxigenic Bacteroides fragilis (ETBF) is highly associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC), rapidly inducing IL-17-dependent murine colitis and tumorigenesis. In specific-pathogen-free (SPF) C57BL/6 wild-type (WT) and multiple intestinal neoplasia (MinApc716+/−) mice, we show that sequential treatment of the NTBF strain, 9343, followed by the ETBF strain, 86-5443-2-2 (86), diminished colitis and tumorigenesis. Mice treated simultaneously with 9343 and 86 exhibited both severe colitis and tumorigenesis. Abrogated disease severity in sequentially treated mice was attributed to 9343 strain dominance and decreased IL-17A, but 86 colonization prior to or simultaneous with 9343 mitigated the anti-inflammatory effect of 9343. Remarkably, 9343-mediated protection was independent of PSA, as sequentially treated mice receiving ΔPSA 9343 exhibited similar protection. Further, SPF WT and Min mice colonized with PSA-competent or PSA-deficient 9343 exhibited similar IL-10, IL-17, and IFN-γ responses. Treatment of 86-colonized mice with 9343 failed to disrupt 86 pathogenesis. Our findings demonstrate that 9343 colonization, independent of PSA, offers prophylaxis against colitis-inducing 86 but may not be a valid therapy once colitis is established.

    更新日期:2018-10-03
  • NLRC4 suppresses IL-17A-mediated neutrophil-dependent host defense through upregulation of IL-18 and induction of necroptosis during Gram-positive pneumonia
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-02
    Sagar Paudel, Laxman Ghimire, Liliang Jin, Pankaj Baral, Shanshan Cai, Samithamby Jeyaseelan

    Gram-positive pathogens, including Staphylococcus aureus, cause necrotizing pneumonia. The central feature of S. aureus pneumonia is toxin-induced necroptosis of immune and resident cells, which impedes host defense. However, the role of the NLRC4 in the lung following S. aureus infection remains elusive. Here, we demonstrate that S. aureus activates the NLRC4 to drive necroptosis and IL-18 production, which impaired IL-17A-dependent neutrophil-mediated host susceptibility. In particular, Nlrc4−/− mice exhibit reduced necroptosis, enhanced neutrophil influx into the lungs, decreased bacterial burden, and improved host survival. Loss of NLRC4 signaling in both hematopoietic and non-hematopoietic cells contributes to the host protection against S. aureus pneumonia. Secretion of IL-17A by γδ T cells is essential for neutrophil recruitment into the lungs of Nlrc4−/− mice following infection. Moreover, treatment of wild-type mice with necroptosis inhibitors or genetic ablation of MLKL and IL-18 improves host defense against S. aureus infection, which is associated with increased IL-17A+γδ T cells and neutrophils. Taken together, these novel findings reveal that S. aureus activates the NLRC4 to dampen IL-17A-dependent neutrophil accumulation through induction of necroptosis and IL-18. Thus, modulating the function of the NLRC4 may be an attractive therapeutic approach for treating S. aureus infections.

    更新日期:2018-10-03
  • Airway epithelial cells prime plasmacytoid dendritic cells to respond to pathogens via secretion of growth factors
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-10-02
    Farah Rahmatpanah, Sudhanshu Agrawal, Natasha Jaiswal, Hannah M. Ngyuen, Michael McClelland, Anshu Agrawal

    Plasmacytoid dendritic cells (PDCs) are critical for defense against respiratory viruses because of their propensity to secrete high levels of type I interferons (IFN). The functions of PDCs in the lung can be influenced by airway epithelial cells. We examined the effect of human primary bronchial epithelial cells (PBECs) on PDC functions by performing RNA-sequencing of PDCs after co-culture with air liquid interface differentiated PBECs. Functional analysis revealed that PDCs co-cultured with PBECs displayed upregulation of type I IFN production and response genes. Upregulated transcripts included those encoding cytosolic sensors of DNA, ZBP-1,IRF-3, and NFkB as well as genes involved in amplification of the IFN response, such as IFNAR1, JAK/STAT, ISG15. In keeping with the RNA-seq data, we observe increased secretion of type I IFN and other cytokines in response to influenza in PDCs co-cultured with PBECs. The PDCs also primed Th1 responses in T cells. The enhanced response of PDCs co-cultured with PBECs was due to the action of growth factors, GMCSF, GCSF, and VEGF, which were secreted by PBECs on differentiation. These data highlight possible mechanisms to enhance the production of type-I IFN in the airways, which is critical for host defense against respiratory infections.

    更新日期:2018-10-02
  • E. coli Nissle 1917 is a safe mucosal delivery vector for a birch-grass pollen chimera to prevent allergic poly-sensitization
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-09-21
    P. J. Sarate, S. Heinl, S. Poiret, M. Drinić, C. Zwicker, I. Schabussova, C. Daniel, U. Wiedermann

    Allergic poly-sensitization affects a large number of allergic patients and poses a great challenge for their treatment. In this study we evaluated the effects of the probiotic Escherichia coli Nissle 1917 (EcN) expressing a birch and grass pollen allergen chimera ‘Bet v 1, Phl p 1 and Phl p 5’ (EcN-Chim) on allergy prevention after oral or intranasal application in poly-sensitized mice. In contrast to oral application, intranasal pretreatment with EcN-Chim prior to poly-sensitization led to a significant reduction of lung inflammation (eosinophils, IL-5, and IL-13 in bronchoalveolar lavage) along with suppressed levels of allergen-specific serum IgE. The suppression was associated with increased levels of allergen-specific IgA in lungs and serum IgG2a along with increased Foxp3, TGF-β, and IL-10 mRNA in bronchial lymph nodes. In vitro EcN induced high levels of IL-10 and IL-6 in both lung and intestinal epithelial cells. Importantly, using in vivo imaging techniques we demonstrated that intranasally applied EcN do not permanently colonize nose, lung, and gut and this strain might therefore be a safe delivery vector against allergy in humans. In conclusion, our data show that intranasal application of recombinant EcN expressing a multiallergen chimera presents a novel and promising treatment strategy for prevention of allergic poly-sensitization.

    更新日期:2018-09-22
  • Low nadir CD4+ T-cell counts predict gut dysbiosis in HIV-1 infection
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-08-31
    Yolanda Guillén, Marc Noguera-Julian, Javier Rivera, Maria Casadellà, Alexander S. Zevin, Muntsa Rocafort, Mariona Parera, Cristina Rodríguez, Marçal Arumí, Jorge Carrillo, Beatriz Mothe, Carla Estany, Josep Coll, Isabel Bravo, Cristina Herrero, Jorge Saz, Guillem Sirera, Ariadna Torrella, Jordi Navarro, Manuel Crespo, Eugènia Negredo, Christian Brander, Julià Blanco, Maria Luz Calle, Nichole R. Klatt, Bonaventura Clotet, Roger Paredes

    Human immunodeficiency virus (HIV)-1 infection causes severe gut and systemic immune damage, but its effects on the gut microbiome remain unclear. Previous shotgun metagenomic studies in HIV-negative subjects linked low-microbial gene counts (LGC) to gut dysbiosis in diseases featuring intestinal inflammation. Using a similar approach in 156 subjects with different HIV-1 phenotypes, we found a strong, independent, dose–effect association between nadir CD4+ T-cell counts and LGC. As in other diseases involving intestinal inflammation, the gut microbiomes of subjects with LGC were enriched in gram-negative Bacteroides, acetogenic bacteria and Proteobacteria, which are able to metabolize reactive oxygen and nitrogen species; and were depleted in oxygen-sensitive methanogenic archaea and sulfate-reducing bacteria. Interestingly, subjects with LGC also showed increased butyrate levels in direct fecal measurements, consistent with enrichment in Roseburia intestinalis despite reductions in other butyrate producers. The microbiomes of subjects with LGC were also enriched in bacterial virulence factors, as well as in genes associated with beta-lactam, lincosamide, tetracycline, and macrolide resistance. Thus, low nadir CD4+ T-cell counts, rather than HIV-1 serostatus per se, predict the presence of gut dysbiosis in HIV-1 infected subjects. Such dysbiosis does not display obvious HIV-specific features; instead, it shares many similarities with other diseases featuring gut inflammation.

    更新日期:2018-09-01
  • The increased protection and pathology in Mycobacterium tuberculosis-infected IL-27R-alpha-deficient mice is supported by IL-17A and is associated with the IL-17A-induced expansion of multifunctional T cells
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-05-04
    Hanna Erdmann, Jochen Behrends, Kristina Ritter, Alexandra Hölscher, Johanna Volz, Ida Rosenkrands, Christoph Hölscher

    During Mycobacterium tuberculosis (Mtb) infection, mice lacking the IL-27R exhibit lower bacterial burdens but develop an immunopathological sequelae in comparison to wild-type mice. We here show that this phenotype correlates with an enhanced recruitment of antigen-specific CCR6+ CD4+ T cells and an increased frequency of IL-17A-producing CD4+ T cells. By comparing the outcome of Mtb infection in C57BL/6, IL-27R-deficient and IL-27R/IL-17A-double deficient mice, we observed that both the increased protection and elevated immunopathology are supported by IL-17A. Whereas IL-17A neither impacts the development of Tr1 cells nor the expression of PD1 and KLRG1 on T cells in IL-27R-deficient mice during infection, it regulates the presence of multifunctional T-cells in the lungs, co-expressing IFN-γ, IL-2 and TNF. Eventually, IL-17A supports Cxcl9, Cxcl10 and Cxcl13 expression and the granulomatous response in the lungs of infected IL-27R-deficient mice. Taken together, IL-17A contributes to protection in Mtb-infected IL-27R-deficient mice probably through a chemokine-mediated recruitment and strategic positioning of multifunctional T cells in granulomas. As IL-27 limits optimal antimycobacterial protection by inhibiting IL-17A production, blocking of IL-27R-mediated signaling may represent a strategy for improving vaccination and host-directed therapy in tuberculosis. However, because IL-27 also prevents IL-17A-mediated immunopathology, such intervention has to be tightly controlled.

    更新日期:2018-05-04
  • Interleukin-22-deficiency and microbiota contribute to the exacerbation of Toxoplasma gondii-induced intestinal inflammation
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-05-04
    A Couturier-Maillard, N Froux, J Piotet-Morin, C Michaudel, L Brault, J Le Bérichel, A Sénéchal, P Robinet, P Chenuet, S Jejou, L Dumoutier, J C Renauld, J Iovanna, S Huber, VFJ Quesniaux, H Sokol, B Ryffel

    Upon oral infection with Toxoplasma gondii cysts (76 K strain) tachyzoites are released into the intestinal lumen and cross the epithelial barrier causing damage and acute intestinal inflammation in C57BL/6 (B6) mice. Here we investigated the role of microbiota and IL-22 in T.gondii-induced small intestinal inflammation. Oral T.gondii infection in B6 mice causes inflammation with IFNγ and IL-22 production. In IL-22-deficient mice, T.gondii infection augments the Th1 driven inflammation. Deficiency in either IL-22bp, the soluble IL-22 receptor or Reg3γ, an IL-22-dependent antimicrobial lectin/peptide, did not reduce inflammation. Under germ-free conditions, T.gondii-induced inflammation was reduced in correlation with parasite load. But intestinal inflammation is still present in germ-free mice, at low level, in the lamina propria, independently of IL-22 expression. Exacerbated intestinal inflammation driven by absence of IL-22 appears to be independent of IL-22 deficiency associated-dysbiosis as similar inflammation was observed after fecal transplantation of IL-22-/- or WT microbiota to germ-free-WT mice. Our results suggest cooperation between parasite and intestinal microbiota in small intestine inflammation development and endogenous IL-22 seems to exert a protective role independently of its effect on the microbiota. In conclusion, IL-22 participates in T.gondii induced acute small intestinal inflammation independently of microbiota and Reg3γ.

    更新日期:2018-05-04
  • A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-05-04
    Jonathan C. Jeschke, Christopher G. Mayne, Jennifer Ziegelbauer, Christopher L. DeCiantis, Selina Singh, Suresh N. Kumar, Mariko Suchi, Yoichiro Iwakura, William R. Drobyski, Nita H Salzman, Calvin B. Williams

    Homeostasis in the ileum, which is commonly disrupted in patients with Crohn’s disease, involves ongoing immune responses. To study how homeostatic processes of the ileum impact CD4+T cell responses, we used TCR transgenic tools to breed mice that spontaneously produced CD4+T cells reactive to an antigen expressed in the ileum. At an early age, the ilea of these mice exhibit crypt hyperplasia and accumulate increased numbers of TH17 cells bearing non-transgenic clonotypes. Half of these mice subsequently developed colitis linked to broad mucosal infiltration by TH17 and TH1 cells expressing non-transgenic clonotypes, chronic wasting disease and loss of ileal crypt hyperplasia. By contrast, adult mice with normal growth continued to exhibit TH17-associated ileal crypt hyperplasia and additionally accumulated ileal-reactive Treg cells. Both IL-17A and IFNγ were protective, as their deficiency precluded ileal-reactive Treg accumulation and exacerbated colitic disease. IL-23R blockade prevented progression to colitis, whereas nTreg cell transfers prevented colitic disease, ileal crypt hyperplasia and ileal-reactive Treg accumulation. Thus, our studies identify an IL-17A and IFNγ-dependent homeostatic process that mobilizes ileal-reactive Treg cells and is disrupted by IL-23.

    更新日期:2018-05-04
  • Charles D. Surh, PhD: 1961–2017
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-04-27
    Hilde Cheroutre

    Charles D. Surh, PhD: 1961–2017Charles D. Surh, PhD: 1961–2017, Published online: 27 April 2018; doi:10.1038/mi.2017.115Charles D. Surh, PhD: 1961–2017

    更新日期:2018-04-27
  • Pulmonary Regnase-1 orchestrates the interplay of epithelium and adaptive immune systems to protect against pneumonia
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-04-25
    Yoshinari Nakatsuka, Alexis Vandenbon, Takashi Mino, Masanori Yoshinaga, Takuya Uehata, Xiaotong Cui, Ayuko Sato, Tohru Tsujimura, Yutaka Suzuki, Atsuyasu Sato, Tomohiro Handa, Kazuo Chin, Teiji Sawa, Toyohiro Hirai, Osamu Takeuchi

    Inhaled pathogens including Pseudomonas aeruginosa initially encounter airway epithelial cells (AECs), which are poised to evoke cell-intrinsic innate defense, affecting second tier of hematopoietic cell-mediated immune reaction. However, it is largely unknown how pulmonary immune responses mediated by a variety of immune cells are coordinated. Here we show that Regnase-1, an endoribonuclease expressed in AECs and immune cells, plays an essential role in coordinating innate responses and adaptive immunity against P. aeruginosa infection. Intratracheal treatment of mice with heat-killed P. aeruginosa resulted in prolonged disappearance of Regnase-1 consistent with sustained expression of Regnase-1 target inflammatory genes, whereas the transcription factor NF-κB was only transiently activated. AEC-specific deletion of Regnase-1 not only augmented innate defenses against P. aeruginosa but also enhanced secretion of Pseudomonas-specific IgA and Th17 accumulation in the lung, culminating in conferring significant resistance against P. aeruginosa re-infection in vivo. Although Regnase-1 directly controls distinct sets of genes in each of AECs and T cells, degradation of Regnase-1 in both cell types is beneficial for maximizing acquired immune responses. Collectively, these results demonstrate that Regnase-1 orchestrates AEC-mediated and immune cell-mediated host defense against pulmonary bacterial infection.

    更新日期:2018-04-25
  • A screen of Crohn’s disease-associated microbial metabolites identifies ascorbate as a novel metabolic inhibitor of activated human T cells
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-04-25
    Yu-Ling Chang, Maura Rossetti, Hera Vlamakis, David Casero, Gemalene Sunga, Nicholas Harre, Shelley Miller, Romney Humphries, Thaddeus Stappenbeck, Kenneth W. Simpson, R. Balfour Sartor, Gary Wu, James Lewis, Frederic Bushman, Dermot P. B. McGovern, Nita Salzman, James Borneman, Ramnik Xavier, Curtis Huttenhower, Jonathan Braun

    Microbial metabolites are an emerging class of mediators influencing CD4+ T-cell function. To advance the understanding of direct causal microbial factors contributing to Crohn’s disease, we screened 139 predicted Crohn’s disease-associated microbial metabolites for their bioactivity on human CD4+ T-cell functions induced by disease-associated T helper 17 (Th17) polarizing conditions. We observed 15 metabolites with CD4+ T-cell bioactivity, 3 previously reported, and 12 unprecedented. A deeper investigation of the microbe-derived metabolite, ascorbate, revealed its selective inhibition on activated human CD4+ effector T cells, including IL-17A-, IL-4-, and IFNγ-producing cells. Mechanistic assessment suggested the apoptosis of activated human CD4+ T cells associated with selective inhibition of energy metabolism. These findings suggest a substantial rate of relevant T-cell bioactivity among Crohn’s disease-associated microbial metabolites, and evidence for novel modes of bioactivity, including targeting of T-cell energy metabolism.

    更新日期:2018-04-25
  • Human intraepithelial lymphocytes
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-04-20
    Toufic Mayassi, Bana Jabri

    The location of intraepithelial lymphocytes (IEL) between epithelial cells, their effector memory, cytolytic and inflammatory phenotype positions them to kill infected epithelial cells and protect the intestine against pathogens. Human TCRαβ+CD8αβ+ IEL have the dual capacity to recognize modified self via natural killer (NK) receptors (autoreactivity) as well as foreign antigen via the T cell receptor (TCR), which is accomplished in mouse by two cell subsets, the naturally occurring TCRαβ+CD8αα+ and adaptively induced TCRαβ+CD8αβ+ IEL subsets, respectively. The private/oligoclonal nature of the TCR repertoire of both human and mouse IEL suggests local environmental factors dictate the specificity of IEL responses. The line between sensing of foreign antigens and autoreactivity is blurred for IEL in celiac disease, where recognition of stress ligands by induced activating NK receptors in conjunction with inflammatory signals such as IL-15 can result in low-affinity TCR/non-cognate antigen and NK receptor/stress ligand interactions triggering destruction of intestinal epithelial cells.

    更新日期:2018-04-20
  • Aryl hydrocarbon receptor and intestinal immunity
    Mucosal Immunol. (IF 7.36) Pub Date : 2018-04-07
    Bruno Lamas, Jane M. Natividad, Harry Sokol

    Aryl hydrocarbon receptor (AhR) is a member of the basic helix–loop–helix–(bHLH) superfamily of transcription factors, which are associated with cellular responses to environmental stimuli, such as xenobiotics and oxygen levels. Unlike other members of bHLH, AhR is the only bHLH transcription factor that is known to be ligand activated. Early AhR studies focused on understanding the role of AhR in mediating the toxicity and carcinogenesis properties of the prototypic ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In recent years, however, it has become apparent that, in addition to its toxicological involvement, AhR is highly receptive to a wide array of endogenous and exogenous ligands, and that its activation leads to a myriad of key host physiological functions. In this study, we review the current understanding of the functions of AhR in the mucosal immune system with a focus on its role in intestinal barrier function and intestinal immune cells, as well as in intestinal homeostasis.

    更新日期:2018-04-07
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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Nature
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华中师范大学化学生物学中心招聘化学类博士后
哈尔滨工业大学刘绍琴教授课题组诚招博士后、科研助理
南方科技大学讲座教授郑智平团队——行政秘书招聘启事
南开化学40万年薪全年诚聘助理研究员(博士后)
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