26 results on '"Hinterleitner R"'
Search Results
2. Cbl-b mediates TGF?² sensitivity by downregulating inhibitory SMAD7 in primary T cells
- Author
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Gruber, T., Hinterleitner, R., Hermann-Kleiter, N., Meisel, M., Kleiter, I., Wang, C. M., Viola, A., Pfeifhofer-Obermair, C., and Baier, G.
- Published
- 2013
- Full Text
- View/download PDF
3. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease
- Author
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Mine R. Ikizler, Fengling Hu, Matthew A. Zurenski, Bana Jabri, Karl W. Boehme, Hans Christian Reinecker, Chaitan Khosla, Brad A. Palanski, Sangman M. Kim, Romain Bouziat, Jason A. Iskarpatyoti, Valentina Discepolo, Ian Lawrence, Jordan D. Ernest, Léa M.M. Costes, Valérie Abadie, Mukund Varma, Janneke N. Samsom, Terence S. Dermody, Solomiia Khomandiak, Ramnik J. Xavier, Carol E. Semrad, Marlies Meisel, Andrea J. Pruijssers, Jennifer E. Stencel-Baerenwald, Nicole McAllister, Sonia S. Kupfer, Reinhard Hinterleitner, Toufic Mayassi, Pavithra Aravamudhan, Stefano Guandalini, Luis B. Barreiro, Judy J. Brown, Aylwin Ng, Bouziat, R., Hinterleitner, R., Brown, J. J., Stencel-Baerenwald, J. E., Ikizler, M., Mayassi, T., Meisel, M., Kim, S. M., Discepolo, V., Pruijssers, A. J., Ernest, J. D., Iskarpatyoti, J. A., Costes, L. M. M., Lawrence, I., Palanski, B. A., Varma, M., Zurenski, M. A., Khomandiak, S., Mcallister, N., Aravamudhan, P., Boehme, K. W., Hu, F., Samsom, J. N., Reinecker, H. -C., Kupfer, S. S., Guandalini, S., Semrad, C. E., Abadie, V., Khosla, C., Barreiro, L. B., Xavier, R. J., Ng, A., Dermody, T. S., Jabri, B., and Pediatrics
- Subjects
0301 basic medicine ,viruses ,Autoimmunity ,Receptor, Interferon alpha-beta ,Disease ,Mice ,0302 clinical medicine ,Interferon ,Reoviridae Infection ,Pathogen ,Multidisciplinary ,Effector ,Intestine ,Intestines ,medicine.anatomical_structure ,Antigen ,Interferon Type I ,030211 gastroenterology & hepatology ,Genetic Engineering ,Human ,medicine.drug ,Glutens ,Regulatory T cell ,Mice, Transgenic ,Biology ,Reoviridae ,Article ,Virus ,03 medical and health sciences ,Immunity ,Immune Tolerance ,medicine ,Animals ,Humans ,Antigens ,Autoantibodies ,Inflammation ,Transglutaminases ,Animal ,Th1 Cells ,biochemical phenomena, metabolism, and nutrition ,Virology ,Diet ,Reoviridae Infections ,Mice, Inbred C57BL ,Celiac Disease ,Disease Models, Animal ,030104 developmental biology ,IRF1 ,Immunology ,Gluten ,Interferon Regulatory Factor-1 - Abstract
Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD.
- Published
- 2017
4. Epigenetic control of commensal induced Th2 Responses and Intestinal immunopathology.
- Author
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Sangani KA, Parker ME, Anderson HD, Chen L, Pandey SP, Pierre JF, Meisel M, Riesenfeld SJ, Hinterleitner R, and Jabri B
- Abstract
Understanding the initiation of T-helper (Th)-2 immunity is crucial for addressing allergic diseases that have been linked to the commensal microbiota. However, Th2 responses are notably absent from known host-microbiota intestinal immune circuits. Notably, the commensal protist Tritrichomonas induces a transient innate ILC2 circuit rather than a chronic Th2 circuit. Canonical Th2 responses rely on the induction of IL-4 production by innate cells. This study shows that the absence of Tet2 , a DNA demethylase, reprograms naïve T cells to autonomously produce IL-4 upon T cell receptor stimulation, bypassing the need for IL-4 from innate cells for Th2 differentiation. Loss of this checkpoint induces chronic Th2 responses to Tritrichomonas , associated with IL-25-dependent barrier dysfunction and increased susceptibility to allergic pathology in response to dietary antigens., Sentence Summary: Regulation of cell autonomous IL-4 in T cells is critical to prevent dysregulated Th2 immunity to commensals and predisposition to allergy.
- Published
- 2024
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5. Non-Host Factors Influencing Onset and Severity of Celiac Disease.
- Author
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Galipeau HJ, Hinterleitner R, Leonard MM, and Caminero A
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- Humans, Animals, Risk Factors, Genetic Predisposition to Disease, Glutens immunology, Glutens adverse effects, Diet adverse effects, Disease Models, Animal, Celiac Disease immunology, Celiac Disease microbiology, Celiac Disease genetics, Gastrointestinal Microbiome, Severity of Illness Index
- Abstract
Celiac disease (CeD) is a chronic autoimmune condition driven by gluten ingestion in genetically predisposed individuals, resulting in inflammatory lesions in the proximal small intestine. Although the presence of specific HLA-linked haplotypes and gluten consumption are necessary for disease development, they alone do not account for the variable onset of CeD in susceptible individuals. This review explores the multifaceted role of non-host factors in CeD development, including dietary and microbial influences. We discuss clinical associations and observations highlighting the impact of these factors on disease onset and severity. Furthermore, we discuss studies in CeD-relevant animal models that offer mechanistic insights into how diet, the microbiome, and enteric infections modulate CeD pathogenesis. Finally, we address the clinical implications and therapeutic potential of understanding these cofactors offering a promising avenue for preventive and therapeutic interventions in CeD management., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
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6. The gut protist Tritrichomonas arnold restrains virus-mediated loss of oral tolerance by modulating dietary antigen-presenting dendritic cells.
- Author
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Medina Sanchez L, Siller M, Zeng Y, Brigleb PH, Sangani KA, Soto AS, Engl C, Laughlin CR, Rana M, Van Der Kraak L, Pandey SP, Bender MJ, Fitzgerald B, Hedden L, Fiske K, Taylor GM, Wright AP, Mehta ID, Rahman SA, Galipeau HJ, Mullett SJ, Gelhaus SL, Watkins SC, Bercik P, Nice TJ, Jabri B, Meisel M, Das J, Dermody TS, Verdú EF, and Hinterleitner R
- Subjects
- Animals, Mice, Humans, Diet, Glutens, Dendritic Cells, Immune Tolerance, Antigens, Immunity, Innate
- Abstract
Loss of oral tolerance (LOT) to gluten, driven by dendritic cell (DC) priming of gluten-specific T helper 1 (Th1) cell immune responses, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. Whether certain commensals can moderate virus-mediated LOT remains elusive. Here, using a mouse model of virus-mediated LOT, we discovered that the gut-colonizing protist Tritrichomonas (T.) arnold promotes oral tolerance and protects against reovirus- and murine norovirus-mediated LOT, independent of the microbiota. Protection was not attributable to antiviral host responses or T. arnold-mediated innate type 2 immunity. Mechanistically, T. arnold directly restrained the proinflammatory program in dietary antigen-presenting DCs, subsequently limiting Th1 and promoting regulatory T cell responses. Finally, analysis of fecal microbiomes showed that T. arnold-related Parabasalid strains are underrepresented in human CeD patients. Altogether, these findings will motivate further exploration of oral-tolerance-promoting protists in CeD and other immune-mediated food sensitivities., Competing Interests: Declaration of interests E.F.V. is a member of the Biocodex International and National (Canada) Scientific Review Boards, a member of the Center for Gut Microbiome Research and Education Scientific Advisory Board of the AGA, Secretary of the International Society of the Study of Celiac Disease, and holds grants from Kallyope and Codexis, unrelated to this study. H.J.G. holds a grant from Codexis, unrelated to this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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7. Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment.
- Author
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Bender MJ, McPherson AC, Phelps CM, Pandey SP, Laughlin CR, Shapira JH, Medina Sanchez L, Rana M, Richie TG, Mims TS, Gocher-Demske AM, Cervantes-Barragan L, Mullett SJ, Gelhaus SL, Bruno TC, Cannon N, McCulloch JA, Vignali DAA, Hinterleitner R, Joglekar AV, Pierre JF, Lee STM, Davar D, Zarour HM, and Meisel M
- Subjects
- Humans, Diet, Immune Checkpoint Inhibitors, Tryptophan metabolism, CD8-Positive T-Lymphocytes immunology, Receptors, Aryl Hydrocarbon agonists, Limosilactobacillus reuteri metabolism, Melanoma therapy, Tumor Microenvironment
- Abstract
The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated Lr's antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 T cell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients., Competing Interests: Declaration of interests D.A.A.V.: cofounder and stock holder—Novasenta, Tizona, Trishula; stock holder—Oncorus, Werewolf; patents licensed and royalties—Novasenta, BMS; scientific advisory board member—Tizona, Werewolf, F-Star, Bicara, Apeximmune, T7/Imreg Bio; consultant—BMS, Almirall, Incyte, G1 Therapeutics, Inzen Therapeutics, Regeneron, Avidity Partners; research funding—BMS, Novasenta. A.V.J.: research funding—Mitsubishi Tanabe Pharma. J.F.P.: cofounder and stock holder—Gateway Biome Corporation. D.D.: grants/research support (institutional)—Arcus, CellSight Technologies, Immunocore, Merck, Regeneron Pharmaceuticals Inc., Tesaro/GSK; consultant: Clinical Care Options (CCO), Finch Therapeutics, Gerson Lehrman Group (GLG), Medical Learning Group (MLG), Xilio Therapeutics; CE Speakers’ Bureau—Castle Biosciences; intellectual Property includes US Patent 63/124,231, “compositions and methods for treating cancer,” December 11, 2020 and US Patent 63/208,719, “compositions and methods for determining responsiveness to immune checkpoint inhibitors (ICIs), increasing effectiveness of ICI and treating cancer,” June 9, 2021., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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8. NK cells contribute to reovirus-induced IFN responses and loss of tolerance to dietary antigen.
- Author
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Brigleb PH, Kouame E, Fiske KL, Taylor GM, Urbanek K, Medina Sanchez L, Hinterleitner R, Jabri B, and Dermody TS
- Subjects
- Animals, Antibodies, Viral, Mice, Immune Tolerance, Killer Cells, Natural
- Abstract
Celiac disease is an immune-mediated intestinal disorder that results from loss of oral tolerance (LOT) to dietary gluten. Reovirus elicits inflammatory Th1 cells and suppresses Treg responses to dietary antigen in a strain-dependent manner. Strain type 1 Lang (T1L) breaks oral tolerance, while strain type 3 Dearing reassortant virus (T3D-RV) does not. We discovered that intestinal infection by T1L in mice leads to the recruitment and activation of NK cells in mesenteric lymph nodes (MLNs) in a type I IFN-dependent manner. Once activated following infection, NK cells produce type II IFN and contribute to IFN-stimulated gene expression in the MLNs, which in turn induces inflammatory DC and T cell responses. Immune depletion of NK cells impairs T1L-induced LOT to newly introduced food antigen. These studies indicate that NK cells modulate the response to dietary antigen in the presence of a viral infection.
- Published
- 2022
- Full Text
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9. Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis.
- Author
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Pandey SP, Bender MJ, McPherson AC, Phelps CM, Sanchez LM, Rana M, Hedden L, Sangani KA, Chen L, Shapira JH, Siller M, Goel C, Verdú EF, Jabri B, Chang A, Chandran UR, Mullett SJ, Wendell SG, Singhi AD, Tilstra JS, Pierre JF, Arteel GE, Hinterleitner R, and Meisel M
- Subjects
- Animals, Dysbiosis complications, Interferon-gamma, Ligands, Mice, T-Lymphocytes, Cytotoxic, DNA-Binding Proteins genetics, Dioxygenases genetics, Hepatitis, Autoimmune etiology, Hepatitis, Autoimmune pathology, Limosilactobacillus reuteri, Liver immunology, Liver microbiology, Microbiota genetics, Microbiota immunology
- Abstract
The triggers that drive interferon-γ (IFNγ)-producing CD8 T cell (Tc1 cell)-mediated autoimmune hepatitis (AIH) remain obscure. Here, we show that lack of hematopoietic Tet methylcytosine dioxygenase 2 (Tet2), an epigenetic regulator associated with autoimmunity, results in the development of microbiota-dependent AIH-like pathology, accompanied by hepatic enrichment of aryl hydrocarbon receptor (AhR) ligand-producing pathobionts and rampant Tc1 cell immunity. We report that AIH-like disease development is dependent on both IFNγ and AhR signaling, as blocking either reverts ongoing AIH-like pathology. Illustrating the critical role of AhR-ligand-producing pathobionts in this condition, hepatic translocation of the AhR ligand indole-3-aldehyde (I3A)-releasing Lactobacillus reuteri is sufficient to trigger AIH-like pathology. Finally, we demonstrate that I3A is required for L. reuteri-induced Tc1 cell differentiation in vitro and AIH-like pathology in vivo, both of which are restrained by Tet2 within CD8 T cells. This AIH-disease model may contribute to the development of therapeutics to alleviate AIH., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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10. Can Microbes Boost Tregs to Suppress Food Sensitivities?
- Author
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Siller M, Zeng Y, and Hinterleitner R
- Subjects
- Cell Proliferation, Food Hypersensitivity prevention & control, Humans, Immune Tolerance immunology, Diet, Food Hypersensitivity immunology, Food Hypersensitivity microbiology, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory immunology
- Abstract
Food sensitivities are on the rise worldwide. Peripheral induced regulatory T cells (pTreg cells) play a central role in oral tolerance to dietary antigens and can contribute to preventing the onset of immune-mediated food sensitivities. Here, we discuss the potential of microbial-derived products in promoting pTreg cell proliferation for re-establishing oral tolerance in immune-mediated food sensitivities., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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11. High-sensitivity C-reactive protein is associated with clonal hematopoiesis of indeterminate potential.
- Author
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Busque L, Sun M, Buscarlet M, Ayachi S, Feroz Zada Y, Provost S, Bourgoin V, Mollica L, Meisel M, Hinterleitner R, Jabri B, Dubé MP, and Tardif JC
- Subjects
- Aged, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Hematopoietic Stem Cells, Humans, Male, C-Reactive Protein, Clonal Hematopoiesis, Hematopoiesis genetics, Percutaneous Coronary Intervention
- Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is predictive of hematological cancers and cardiovascular diseases, but the etiology of CHIP initiation and clonal expansion is unknown. Several lines of evidence suggest that proinflammatory cytokines may favor mutated hematopoietic stem cell expansion. To investigate the potential link between inflammation and CHIP, we performed targeted deep sequencing of 11 genes previously implicated in CHIP in 1887 subjects aged >70 years from the Montreal Heart Institute Biobank, of which 1359 had prior coronary artery disease (CAD), and 528 controls did not. We assessed association of CHIP with log transformed high-sensitivity C-reactive protein (hs-CRP), a validated biomarker of inflammation. CHIP was identified in 427 of the 1887 subjects (22.6%). CHIP mutations were more frequently identified in DNMT3A (11.6%) and TET2 (6.1%), with a higher proportion of TET2 mutations occurring in controls than in patients with CAD (9.0% vs 4.9%, P < .001). CHIP carriers had 21% higher hs-CRP levels compared with their noncarrier counterparts (eβ = 1.21, 95% confidence interval [CI]: 1.08 to 1.36; P = .001). A similar effect was observed in the subgroup of patients with known CAD (eβ = 1.22, 95% CI: 1.06 to 1.41; P = .005). These findings confirm the association between inflammation and CHIP. This association may open investigational avenues aimed at documenting mechanisms linking inflammation to clonal progression and ultimately supports prevention interventions to attenuate CHIP's impact on cardiovascular disease and cancer., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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12. Murine Norovirus Infection Induces T H 1 Inflammatory Responses to Dietary Antigens.
- Author
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Bouziat R, Biering SB, Kouame E, Sangani KA, Kang S, Ernest JD, Varma M, Brown JJ, Urbanek K, Dermody TS, Ng A, Hinterleitner R, Hwang S, and Jabri B
- Subjects
- Administration, Oral, Animals, Caliciviridae Infections virology, Capsid Proteins immunology, Celiac Disease immunology, Disease Models, Animal, Female, HEK293 Cells, Humans, Immunity, Inflammation, Interferon Regulatory Factor-1 immunology, Lymph Nodes, Mice, Mice, Inbred C57BL, Ovalbumin administration & dosage, Virus Shedding, Caliciviridae Infections immunology, Diet, Norovirus immunology, Norovirus pathogenicity, Ovalbumin immunology, Th1 Cells immunology
- Abstract
Intestinal reovirus infection can trigger T helper 1 (T
H 1) immunity to dietary antigen, raising the question of whether other viruses can have a similar impact. Here we show that the acute CW3 strain of murine norovirus, but not the persistent CR6 strain, induces TH 1 immunity to dietary antigen. This property of CW3 is dependent on its major capsid protein, a virulence determinant. Transcriptional profiling of mesenteric lymph nodes following infection reveals an immunopathological signature that does not segregate with protective immunity but with loss of oral tolerance, in which interferon regulatory factor 1 is critical. These data show that viral capacity to trigger specific inflammatory pathways at sites where T cell responses to dietary antigens take place interferes with the development of tolerance to an oral antigen. Collectively, these data provide a foundation for the development of therapeutic strategies to prevent TH 1-mediated complex immune disorders triggered by viral infections., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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13. Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-b.
- Author
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Peer S, Cappellano G, Hermann-Kleiter N, Albrecht-Schgoer K, Hinterleitner R, Baier G, and Gruber T
- Subjects
- Animals, Autoimmunity genetics, Gene Expression Regulation, Interleukin-3 genetics, Mice, Inbred C57BL, Mice, Knockout, Promoter Regions, Genetic, Adaptor Proteins, Signal Transducing physiology, CD4-Positive T-Lymphocytes metabolism, Encephalomyelitis, Autoimmune, Experimental immunology, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Proto-Oncogene Proteins c-cbl physiology
- Abstract
Genome-wide association studies as well as lymphatic expression analyses have linked both Cbl-b and GM-CSF to human multiple sclerosis as well as other autoimmune diseases. Both Cbl-b and GM-CSF have been shown to play a prominent role in the development of murine encephalomyelitis; however, no functional connection between the two has yet been established. In this study, we show that Cblb knockout mice demonstrated significantly exacerbated severity of experimental autoimmune encephalomyelitis (EAE), augmented T cell infiltration into the central nervous system (CNS) and strongly increased production of GM-CSF in T cells in vitro and in vivo .GM-CSF neutralization demonstrated that the increased susceptibility of Cblb
-/- mice to EAE was dependent on GM-CSF. Mechanistically, p50 binding to the GM-CSF promoter and the IL-3/GM-CSF enhancer element "CNSa" was strongly increased in nuclear extracts from Cbl-b-deficient T cells. This study suggests that Cbl-b limits autoimmunity by preventing the pathogenic effects of GM-CSF overproduction in T cells.- Published
- 2018
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14. Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes.
- Author
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Konjar Š, Frising UC, Ferreira C, Hinterleitner R, Mayassi T, Zhang Q, Blankenhaus B, Haberman N, Loo Y, Guedes J, Baptista M, Innocentin S, Stange J, Strathdee D, Jabri B, and Veldhoen M
- Subjects
- Animals, Cardiolipins metabolism, Cells, Cultured, Coccidiosis parasitology, Disease Models, Animal, Eimeria immunology, Female, Humans, Intestinal Mucosa immunology, Intraepithelial Lymphocytes cytology, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Transmission, Mitochondria immunology, Mitochondria ultrastructure, Mitochondrial Membranes immunology, Mitochondrial Membranes metabolism, Mitochondrial Membranes ultrastructure, Primary Cell Culture, T-Lymphocytes cytology, Coccidiosis immunology, Intestinal Mucosa cytology, Intraepithelial Lymphocytes immunology, Mitochondria metabolism, T-Lymphocytes immunology
- Abstract
Epithelial-resident T lymphocytes, such as intraepithelial lymphocytes (IELs) located at the intestinal barrier, can offer swift protection against invading pathogens. Lymphocyte activation is strictly regulated because of its potential harmful nature and metabolic cost, and most lymphocytes are maintained in a quiescent state. However, IELs are kept in a heightened state of activation resembling effector T cells but without cytokine production or clonal proliferation. We show that this controlled activation state correlates with alterations in the IEL mitochondrial membrane, especially the cardiolipin composition. Upon inflammation, the cardiolipin composition is altered to support IEL proliferation and effector function. Furthermore, we show that cardiolipin makeup can particularly restrict swift IEL proliferation and effector functions, reducing microbial containment capability. These findings uncover an alternative mechanism to control cellular activity, special to epithelial-resident T cells, and a novel role for mitochondria, maintaining cells in a metabolically poised state while enabling rapid progression to full functionality., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
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15. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host.
- Author
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Meisel M, Hinterleitner R, Pacis A, Chen L, Earley ZM, Mayassi T, Pierre JF, Ernest JD, Galipeau HJ, Thuille N, Bouziat R, Buscarlet M, Ringus DL, Wang Y, Li Y, Dinh V, Kim SM, McDonald BD, Zurenski MA, Musch MW, Furtado GC, Lira SA, Baier G, Chang EB, Eren AM, Weber CR, Busque L, Godley LA, Verdú EF, Barreiro LB, and Jabri B
- Subjects
- Animals, Bacterial Infections immunology, Bacterial Infections microbiology, DNA-Binding Proteins genetics, Dioxygenases, Female, Germ-Free Life, Inflammation microbiology, Interleukin-6 immunology, Intestinal Mucosa metabolism, Lactobacillus chemistry, Lactobacillus cytology, Lactobacillus immunology, Male, Mice, Penetrance, Permeability, Proto-Oncogene Proteins genetics, Toll-Like Receptor 2 agonists, Asymptomatic Diseases, Bacterial Physiological Phenomena immunology, Cell Proliferation, DNA-Binding Proteins deficiency, Leukemia microbiology, Leukemia pathology, Proto-Oncogene Proteins deficiency
- Abstract
Somatic mutations in tet methylcytosine dioxygenase 2 (TET2), which encodes an epigenetic modifier enzyme, drive the development of haematopoietic malignancies
1-7 . In both humans and mice, TET2 deficiency leads to increased self-renewal of haematopoietic stem cells with a net developmental bias towards the myeloid lineage1,4,8,9 . However, pre-leukaemic myeloproliferation (PMP) occurs in only a fraction of Tet2-/- mice8,9 and humans with TET2 mutations1,3,5-7 , suggesting that extrinsic non-cell-autonomous factors are required for disease onset. Here we show that bacterial translocation and increased interleukin-6 production, resulting from dysfunction of the small-intestinal barrier, are critical for the development of PMP in mice that lack Tet2 expression in haematopoietic cells. Furthermore, in symptom-free Tet2-/- mice, PMP can be induced by disrupting intestinal barrier integrity, or in response to systemic bacterial stimuli such as the toll-like receptor 2 agonist. PMP was reversed by antibiotic treatment and failed to develop in germ-free Tet2-/- mice, which illustrates the importance of microbial signals in the development of this condition. Our findings demonstrate the requirement for microbial-dependent inflammation in the development of PMP and provide a mechanistic basis for the variation in PMP penetrance observed in Tet2-/- mice. This study will prompt new lines of investigation that may profoundly affect the prevention and management of haematopoietic malignancies.- Published
- 2018
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16. Dietary antioxidant micronutrients alter mucosal inflammatory risk in a murine model of genetic and microbial susceptibility.
- Author
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Pierre JF, Hinterleitner R, Bouziat R, Hubert NA, Leone V, Miyoshi J, Jabri B, and Chang EB
- Subjects
- Animals, Body Weight drug effects, Cytokines metabolism, Disease Models, Animal, Female, Gastrointestinal Microbiome, Genetic Predisposition to Disease, Immunoglobulins metabolism, Inflammatory Bowel Diseases etiology, Inflammatory Bowel Diseases microbiology, Interleukin-10 genetics, Intestinal Mucosa immunology, Intestinal Mucosa pathology, Mice, Inbred C57BL, Mice, Mutant Strains, Selenium pharmacology, T-Lymphocytes drug effects, Vitamins pharmacology, Antioxidants pharmacology, Inflammatory Bowel Diseases diet therapy, Intestinal Mucosa drug effects, Micronutrients pharmacology
- Abstract
Inflammatory bowel diseases (IBD) are caused by the convergence of microbial, environmental, and genetic factors. Diet significantly alters these interactions by affecting both the host and microbiome. Using a mucosal inflammatory model that resembles the human condition of ileal pouchitis, we investigated the effects of Control (CONT) or Antioxidant (AOX) diet, containing pharmacologically relevant levels of 4 micronutrients, on disease risk in wild-type and IL-10
-/- animals following surgical self-filling (SF) ileal blind loop placement. Although no differences were found in body weight change or survival, IL-10-/- CONT animals had significantly larger lymphoid organs compared with IL-10-/- AOX or with WT. SF loops from IL-10-/- CONT loop mucosa demonstrated histological inflammation, characterized by goblet cell depletion, increased mucosal myeloperoxidase (MPO), and elevated IFNγ, TNFα, and IL-17α gene expression, which AOX attenuated. AOX elevated luminal IgA in IL-10-/- animals, but not significantly in WT. In IL-10-/- animals, AOX significantly decreased the percentage of CD4 + T-bet and CD4 + RORγ T-cells compared with CONT, with no changes in CD4 + Foxp3+ Treg cells. 16S rRNA gene sequencing demonstrated AOX increased microbial alpha diversity compared with CONT in both genotypes. Notably, colonizing germ-free IL-10-/- hosts with CONT bacterial communities, but not AOX, recapitulated the inflammatory phenotype. Collectively, these findings highlight that common dietary antioxidant micronutrients reshape the gut microbial community to mitigate intestinal inflammatory profiles in genetically susceptible hosts. Insights into the dietary-immune-microbial nexus may improve understanding for recurrent inflammatory episodes in susceptible patient populations and opportunities for practical therapeutics to restore immune and microbial homeostasis., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2018
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17. Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APP SWE /PS1 ΔE9 murine model of Alzheimer's disease.
- Author
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Minter MR, Hinterleitner R, Meisel M, Zhang C, Leone V, Zhang X, Oyler-Castrillo P, Zhang X, Musch MW, Shen X, Jabri B, Chang EB, Tanzi RE, and Sisodia SS
- Subjects
- Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Protein Precursor metabolism, Amyloidosis metabolism, Amyloidosis pathology, Animals, Biodiversity, Biomarkers, Brain metabolism, Brain pathology, Disease Models, Animal, Gastrointestinal Microbiome, Inflammation Mediators metabolism, Male, Metagenome, Metagenomics methods, Mice, Mice, Transgenic, Neuroimmunomodulation drug effects, Neuroimmunomodulation genetics, Neuroimmunomodulation immunology, Plaque, Amyloid etiology, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, RNA, Ribosomal, 16S genetics, Alzheimer Disease etiology, Amyloid beta-Protein Precursor genetics, Amyloidosis genetics, Anti-Bacterial Agents pharmacology, Microbiota drug effects
- Abstract
Recent evidence suggests the commensal microbiome regulates host immunity and influences brain function; findings that have ramifications for neurodegenerative diseases. In the context of Alzheimer's disease (AD), we previously reported that perturbations in microbial diversity induced by life-long combinatorial antibiotic (ABX) selection pressure in the APP
SWE /PS1ΔE9 mouse model of amyloidosis is commensurate with reductions in amyloid-β (Aβ) plaque pathology and plaque-localised gliosis. Considering microbiota-host interactions, specifically during early post-natal development, are critical for immune- and neuro-development we now examine the impact of microbial community perturbations induced by acute ABX exposure exclusively during this period in APPSWE /PS1ΔE9 mice. We show that early post-natal (P) ABX treatment (P14-P21) results in long-term alterations of gut microbial genera (predominantly Lachnospiraceae and S24-7) and reduction in brain Aβ deposition in aged APPSWE /PS1ΔE9 mice. These mice exhibit elevated levels of blood- and brain-resident Foxp3+ T-regulatory cells and display an alteration in the inflammatory milieu of the serum and cerebrospinal fluid. Finally, we confirm that plaque-localised microglia and astrocytes are reduced in ABX-exposed mice. These findings suggest that ABX-induced microbial diversity perturbations during post-natal stages of development coincide with altered host immunity mechanisms and amyloidosis in a murine model of AD.- Published
- 2017
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18. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease.
- Author
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Bouziat R, Hinterleitner R, Brown JJ, Stencel-Baerenwald JE, Ikizler M, Mayassi T, Meisel M, Kim SM, Discepolo V, Pruijssers AJ, Ernest JD, Iskarpatyoti JA, Costes LM, Lawrence I, Palanski BA, Varma M, Zurenski MA, Khomandiak S, McAllister N, Aravamudhan P, Boehme KW, Hu F, Samsom JN, Reinecker HC, Kupfer SS, Guandalini S, Semrad CE, Abadie V, Khosla C, Barreiro LB, Xavier RJ, Ng A, Dermody TS, and Jabri B
- Subjects
- Animals, Diet adverse effects, Disease Models, Animal, Genetic Engineering, Humans, Immune Tolerance, Inflammation immunology, Interferon Regulatory Factor-1 genetics, Interferon Regulatory Factor-1 immunology, Interferon Type I genetics, Interferon Type I immunology, Intestines immunology, Intestines pathology, Intestines virology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptor, Interferon alpha-beta genetics, Reoviridae genetics, Antigens immunology, Celiac Disease immunology, Celiac Disease virology, Glutens immunology, Inflammation virology, Reoviridae Infections complications, Reoviridae Infections immunology, Th1 Cells immunology
- Abstract
Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (T
H 1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg ) conversion and promoting TH 1 immunity to dietary antigen. Initiation of TH 1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD., (Copyright © 2017, American Association for the Advancement of Science.)- Published
- 2017
- Full Text
- View/download PDF
19. Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis.
- Author
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Meisel M, Mayassi T, Fehlner-Peach H, Koval JC, O'Brien SL, Hinterleitner R, Lesko K, Kim S, Bouziat R, Chen L, Weber CR, Mazmanian SK, Jabri B, and Antonopoulos DA
- Subjects
- Animals, Bacteria classification, Bacteria genetics, Bacteria isolation & purification, Colitis genetics, Colitis microbiology, Colitis therapy, Disease Susceptibility, Dysbiosis genetics, Dysbiosis metabolism, Fecal Microbiota Transplantation, Feces microbiology, Female, Germ-Free Life, Humans, Interleukin-15 genetics, Intestinal Mucosa metabolism, Intestinal Mucosa microbiology, Male, Mice, Mice, Inbred C57BL, Bacteria metabolism, Butyrates metabolism, Colitis metabolism, Dysbiosis microbiology, Gastrointestinal Microbiome, Interleukin-15 metabolism, Intestines microbiology
- Abstract
Dysbiosis resulting in gut-microbiome alterations with reduced butyrate production are thought to disrupt intestinal immune homeostasis and promote complex immune disorders. However, whether and how dysbiosis develops before the onset of overt pathology remains poorly defined. Interleukin-15 (IL-15) is upregulated in distressed tissue and its overexpression is thought to predispose susceptible individuals to and have a role in the pathogenesis of celiac disease and inflammatory bowel disease (IBD). Although the immunological roles of IL-15 have been largely studied, its potential impact on the microbiota remains unexplored. Analysis of 16S ribosomal RNA-based inventories of bacterial communities in mice overexpressing IL-15 in the intestinal epithelium (villin-IL-15 transgenic (v-IL-15tg) mice) shows distinct changes in the composition of the intestinal bacteria. Although some alterations are specific to individual intestinal compartments, others are found across the ileum, cecum and feces. In particular, IL-15 overexpression restructures the composition of the microbiota with a decrease in butyrate-producing bacteria that is associated with a reduction in luminal butyrate levels across all intestinal compartments. Fecal microbiota transplant experiments of wild-type and v-IL-15tg microbiota into germ-free mice further indicate that diminishing butyrate concentration observed in the intestinal lumen of v-IL-15tg mice is the result of intrinsic alterations in the microbiota induced by IL-15. This reconfiguration of the microbiota is associated with increased susceptibility to dextran sodium sulfate-induced colitis. Altogether, this study reveals that IL-15 impacts butyrate-producing bacteria and lowers butyrate levels in the absence of overt pathology, which represent events that precede and promote intestinal inflammatory diseases.
- Published
- 2017
- Full Text
- View/download PDF
20. A dendritic cell subset designed for oral tolerance.
- Author
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Hinterleitner R and Jabri B
- Subjects
- Administration, Oral, Humans, Dendritic Cells, Immune Tolerance
- Published
- 2016
- Full Text
- View/download PDF
21. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells.
- Author
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Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, and Penninger JM
- Subjects
- Adaptor Proteins, Signal Transducing deficiency, Adaptor Proteins, Signal Transducing genetics, Animals, Anticoagulants pharmacology, Anticoagulants therapeutic use, Female, Killer Cells, Natural drug effects, Killer Cells, Natural metabolism, Male, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental genetics, Mammary Neoplasms, Experimental immunology, Melanoma, Experimental drug therapy, Melanoma, Experimental genetics, Melanoma, Experimental immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Metastasis drug therapy, Neoplasm Metastasis prevention & control, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-cbl deficiency, Proto-Oncogene Proteins c-cbl genetics, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Ubiquitin-Protein Ligases deficiency, Ubiquitin-Protein Ligases genetics, Ubiquitination, Warfarin pharmacology, Warfarin therapeutic use, c-Mer Tyrosine Kinase, Axl Receptor Tyrosine Kinase, Adaptor Proteins, Signal Transducing metabolism, Killer Cells, Natural immunology, Mammary Neoplasms, Experimental pathology, Melanoma, Experimental pathology, Neoplasm Metastasis immunology, Proto-Oncogene Proteins c-cbl metabolism, Receptor Protein-Tyrosine Kinases metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.
- Published
- 2014
- Full Text
- View/download PDF
22. Engineering effective T-cell based antitumor immunity.
- Author
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Gruber T, Hinterleitner R, Pfeifhofer-Obermair C, Wolf D, and Baier G
- Abstract
The adoptive transfer of synthetic siRNA-mediated cblb -depleted autologous CD8
+ T cells acts as a potent adjuvant for dendritic cell (DC) vaccination and provides a significant therapeutic benefit. Our proof-of-concept study validates the strategy of inhibiting CBLB as a rational approach to augment the effectiveness of adoptively transferred immune cells.- Published
- 2013
- Full Text
- View/download PDF
23. The kinase PKCα selectively upregulates interleukin-17A during Th17 cell immune responses.
- Author
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Meisel M, Hermann-Kleiter N, Hinterleitner R, Gruber T, Wachowicz K, Pfeifhofer-Obermair C, Fresser F, Leitges M, Soldani C, Viola A, Kaminski S, and Baier G
- Subjects
- Animals, Encephalomyelitis, Autoimmune, Experimental chemically induced, Encephalomyelitis, Autoimmune, Experimental genetics, Encephalomyelitis, Autoimmune, Experimental immunology, Gene Expression Regulation, Interleukin-17 immunology, Mice, Mice, Knockout, Myelin-Oligodendrocyte Glycoprotein adverse effects, Peptide Fragments adverse effects, Protein Kinase C-alpha genetics, Receptors, Transforming Growth Factor beta metabolism, Signal Transduction, Smad Proteins metabolism, Substrate Specificity, Interleukin-17 metabolism, Protein Kinase C-alpha metabolism, Th17 Cells immunology, Th17 Cells metabolism
- Abstract
Transforming growth-factor β (TGFβ) has been implicated in T helper 17 (Th17) cell biology and in triggering expression of interleukin-17A (IL-17A), which is a key Th17 cell cytokine. Deregulated TGFβ receptor (TGFβR) signaling has been implicated in Th17-cell-mediated autoimmune pathogenesis. Nevertheless, the full molecular mechanisms involved in the activation of the TGFβR pathway in driving IL-17A expression remain unknown. Here, we identified protein kinase C α (PKCα) as a signaling intermediate specific to the Th17 cell subset in the activation of TGFβRI. We have shown that PKCα physically interacts and functionally cooperates with TGFβRI to promote robust SMAD2-3 activation. Furthermore, PKCα-deficient (Prkca(-/-)) cells demonstrated a defect in SMAD-dependent IL-2 suppression, as well as decreased STAT3 DNA binding within the Il17a promoter. Consistently, Prkca(-/-) cells failed to mount appropriate IL-17A, but not IL-17F, responses in vitro and were resistant to induction of Th17-cell-dependent experimental autoimmune encephalomyelitis in vivo., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
24. Adoptive transfer of siRNA Cblb-silenced CD8+ T lymphocytes augments tumor vaccine efficacy in a B16 melanoma model.
- Author
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Hinterleitner R, Gruber T, Pfeifhofer-Obermair C, Lutz-Nicoladoni C, Tzankov A, Schuster M, Penninger JM, Loibner H, Lametschwandtner G, Wolf D, and Baier G
- Subjects
- Adaptor Proteins, Signal Transducing antagonists & inhibitors, Adaptor Proteins, Signal Transducing genetics, Animals, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes transplantation, Dendritic Cells immunology, Dendritic Cells metabolism, Female, Gene Silencing, Humans, Melanoma, Experimental immunology, Melanoma, Experimental pathology, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins c-cbl antagonists & inhibitors, Proto-Oncogene Proteins c-cbl genetics, RNA, Small Interfering genetics, RNA, Small Interfering immunology, Skin Neoplasms immunology, Skin Neoplasms pathology, Transforming Growth Factor beta immunology, Adaptor Proteins, Signal Transducing immunology, Adoptive Transfer, CD8-Positive T-Lymphocytes immunology, Cancer Vaccines immunology, Melanoma, Experimental therapy, Proto-Oncogene Proteins c-cbl immunology, Skin Neoplasms therapy
- Abstract
The ubiquitin ligase Cbl-b is an established regulator of T cell immune response thresholds. We recently showed that adoptive cell transfer (ACT) of cblb(-/-) CD8(+) T cells enhances dendritic cell (DC) immunization-mediated anti-tumor effects in immune-competent recipients. However, translation of cblb targeting to clinically applicable concepts requires that inhibition of cblb activity be transient and reversible. Here we provide experimental evidence that inhibition of cblb using chemically synthesized siRNA has such potential. Silencing cblb expression by ex vivo siRNA transfection of polyclonal CD8(+) T cells prior to ACT increased T cell tumor infiltration, significantly delayed tumor outgrowth, and increased survival rates of tumor-bearing mice. As shown by ex vivo recall assays, cblb silencing resulted in significant augmentation of intratumoral T cell cytokine response. ACT of cblb-silenced polyclonal CD8(+) T cells combined with DC-based tumor vaccines predominantly mediated anti-tumor immune responses, whereas no signs of autoimmunity could be detected. Importantly, CBLB silencing in human CD8(+) T cells mirrored the effects observed for cblb-silenced and cblb-deficient murine T cells. Our data validate the concept of enhanced anti-tumor immunity by repetitive ACT of ex vivo cblb siRNA-silenced hyper-reactive CD8(+) T cells as add-on adjuvant therapy to augment the efficacy of existing cancer immunotherapy regimens in clinical practice.
- Published
- 2012
- Full Text
- View/download PDF
25. Essential role of E3 ubiquitin ligase activity in Cbl-b-regulated T cell functions.
- Author
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Paolino M, Thien CB, Gruber T, Hinterleitner R, Baier G, Langdon WY, and Penninger JM
- Subjects
- Adaptor Proteins, Signal Transducing deficiency, Adaptor Proteins, Signal Transducing genetics, Animals, Autoimmune Diseases enzymology, Autoimmune Diseases immunology, Autoimmune Diseases pathology, Cell Line, Tumor, Clonal Anergy genetics, Enzyme Activation genetics, Enzyme Activation immunology, Female, Gene Knock-In Techniques, Immunophenotyping, Lymphocyte Activation genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Point Mutation, Proto-Oncogene Proteins c-cbl deficiency, Proto-Oncogene Proteins c-cbl genetics, RING Finger Domains genetics, T-Lymphocyte Subsets pathology, T-Lymphocytes, Cytotoxic enzymology, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic pathology, Ubiquitin-Protein Ligases genetics, Adaptor Proteins, Signal Transducing physiology, Proto-Oncogene Proteins c-cbl physiology, T-Lymphocyte Subsets enzymology, T-Lymphocyte Subsets immunology, Ubiquitin-Protein Ligases antagonists & inhibitors, Ubiquitin-Protein Ligases physiology
- Abstract
E3 ubiquitin ligases have been placed among the essential molecules involved in the regulation of T cell functions and T cell tolerance. However, it has never been experimentally proven in vivo whether these functions indeed depend on the catalytic E3 ligase activity. The Casitas B-cell lymphoma (Cbl) family protein Cbl-b was the first E3 ubiquitin ligase directly implicated in the activation and tolerance of the peripheral T cell. In this study, we report that selective genetic inactivation of Cbl-b E3 ligase activity phenocopies the T cell responses observed when total Cbl-b is ablated, resulting in T cell hyperactivation, spontaneous autoimmunity, and impaired induction of T cell anergy in vivo. Moreover, mice carrying a Cbl-b E3 ligase-defective mutation spontaneously reject tumor cells that express human papilloma virus Ags. These data demonstrate for the first time, to our knowledge, that the catalytic function of an E3 ligase, Cbl-b, is essential for negative regulation of T cells in vivo. Thus, modulation of the E3 ligase activity of Cbl-b might be a novel modality to control T cell immunity in vaccination, cancer biology, or autoimmunity.
- Published
- 2011
- Full Text
- View/download PDF
26. PKC-theta modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation.
- Author
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Gruber T, Hermann-Kleiter N, Hinterleitner R, Fresser F, Schneider R, Gastl G, Penninger JM, and Baier G
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Animals, CD28 Antigens genetics, CD28 Antigens immunology, CD28 Antigens metabolism, Isoenzymes genetics, Isoenzymes metabolism, Lymphocyte Activation genetics, Mice, Mice, Knockout, Protein Kinase C genetics, Protein Kinase C metabolism, Protein Kinase C-theta, Proto-Oncogene Proteins c-cbl genetics, Proto-Oncogene Proteins c-cbl metabolism, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes enzymology, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Ubiquitination genetics, Adaptor Proteins, Signal Transducing immunology, Isoenzymes immunology, Lymphocyte Activation immunology, Protein Kinase C immunology, Proto-Oncogene Proteins c-cbl immunology, T-Lymphocytes immunology, Ubiquitin-Protein Ligases immunology, Ubiquitination immunology
- Abstract
The E3 ubiquitin ligase Casitas B-lineage lymphoma (Cbl-b) is central to antigen-induced immune tolerance and regulates the CD28 dependence of T cell activation. Cbl-b undergoes ubiquitination and proteasomal degradation after adequate costimulation of T cells; however, the mechanism involved is unknown. Here, we identified protein kinase C-theta (PKC-theta) as the critical intermediary for the inactivation of Cbl-b in response to costimulation of T cells through CD28. PKC-theta associated with Cbl-b on stimulation of the T cell receptor. After costimulation of T cells through CD28, Cbl-b was ubiquitinated and degraded through a mechanism that depended on the kinase activity of PKC-theta. Consistent with this mechanism, the impaired responses of PKCtheta-deficient T cells were at least partially restored by the concomitant genetic loss of cblb. Thus, our data establish a nonredundant antagonism between PKC-theta and Cbl-b that regulates T cell activation responses.
- Published
- 2009
- Full Text
- View/download PDF
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