30 results on '"Perez-Shibayama C"'
Search Results
2. Fibroblastic reticular cell lineage convergence in Peyer’s patches governs intestinal immunity
- Author
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Prados, A. Onder, L. Cheng, H.-W. Mörbe, U. Lütge, M. Gil-Cruz, C. Perez-Shibayama, C. Koliaraki, V. Ludewig, B. Kollias, G.
- Abstract
Fibroblastic reticular cells (FRCs) determine the organization of lymphoid organs and control immune cell interactions. While the cellular and molecular mechanisms underlying FRC differentiation in lymph nodes and the splenic white pulp have been elaborated to some extent, in Peyer’s patches (PPs) they remain elusive. Using a combination of single-cell transcriptomics and cell fate mapping in advanced mouse models, we found that PP formation in the mouse embryo is initiated by an expansion of perivascular FRC precursors, followed by FRC differentiation from subepithelial progenitors. Single-cell transcriptomics and cell fate mapping confirmed the convergence of perivascular and subepithelial FRC lineages. Furthermore, lineage-specific loss- and gain-of-function approaches revealed that the two FRC lineages synergistically direct PP organization, maintain intestinal microbiome homeostasis and control anticoronavirus immune responses in the gut. Collectively, this study reveals a distinct mosaic patterning program that generates key stromal cell infrastructures for the control of intestinal immunity. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature.
- Published
- 2021
3. Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis
- Author
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Brenig, R, Pop, OT, Triantafyllou, E, Geng, A, Singanayagam, A, Perez-Shibayama, C, Besse, L, Cupovic, J, Kuenzler, P, Boldanova, T, Brand, S, Semela, D, Duong, FHT, Weston, CJ, Ludewig, B, Heim, MH, Wendon, J, Antoniades, CG, and Bernsmeier, C
- Subjects
Life Sciences & Biomedicine - Other Topics ,CHRONIC LIVER-FAILURE ,Adult ,Liver Cirrhosis ,Male ,METFORMIN ,THP-1 Cells ,Lymphocyte Activation ,Severity of Illness Index ,BACTERIAL-INFECTIONS ,IMMUNE DYSFUNCTION ,Monocytes ,ACUTE DECOMPENSATION ,INFLAMMATION ,Phagocytosis ,Transduction, Genetic ,Proto-Oncogene Proteins ,APOPTOTIC CELLS ,INTERLEUKIN-1 ,Humans ,MACROPHAGES ,Biology ,Research Articles ,Aged ,Science & Technology ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Receptor Protein-Tyrosine Kinases ,Middle Aged ,Axl Receptor Tyrosine Kinase ,DR EXPRESSION ,Immunity, Innate ,Female ,Life Sciences & Biomedicine ,Biomarkers ,Research Article ,Follow-Up Studies ,Signal Transduction - Abstract
Immune dysfunction determines morbidity and mortality in liver cirrhosis. Distinct AXL-expressing circulating monocytes, which regulate antimicrobial responses, expand with progression of the disease., Infectious complications in patients with cirrhosis frequently initiate episodes of decompensation and substantially contribute to the high mortality. Mechanisms of the underlying immuneparesis remain underexplored. TAM receptors (TYRO3/AXL/MERTK) are important inhibitors of innate immune responses. To understand the pathophysiology of immuneparesis in cirrhosis, we detailed TAM receptor expression in relation to monocyte function and disease severity prior to the onset of acute decompensation. TNF-α/IL-6 responses to lipopolysaccharide were attenuated in monocytes from patients with cirrhosis (n = 96) compared with controls (n = 27) and decreased in parallel with disease severity. Concurrently, an AXL-expressing (AXL+) monocyte population expanded. AXL+ cells (CD14+CD16highHLA-DRhigh) were characterised by attenuated TNF-α/IL-6 responses and T cell activation but enhanced efferocytosis and preserved phagocytosis of Escherichia coli. Their expansion correlated with disease severity, complications, infection, and 1-yr mortality. AXL+ monocytes were generated in response to microbial products and efferocytosis in vitro. AXL kinase inhibition and down-regulation reversed attenuated monocyte inflammatory responses in cirrhosis ex vivo. AXL may thus serve as prognostic marker and deserves evaluation as immunotherapeutic target in cirrhosis.
- Published
- 2019
4. Cardiac Fibroblastic Niches in Homeostasis and Inflammation.
- Author
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Cadosch N, Gil-Cruz C, Perez-Shibayama C, and Ludewig B
- Subjects
- Humans, Animals, Inflammation metabolism, Inflammation pathology, Inflammation immunology, Myocarditis immunology, Myocarditis pathology, Myocarditis metabolism, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Cell Communication, Homeostasis, Fibroblasts metabolism, Fibroblasts pathology, Fibroblasts immunology, Myocardium pathology, Myocardium immunology, Myocardium metabolism
- Abstract
Fibroblasts are essential for building and maintaining the structural integrity of all organs. Moreover, fibroblasts can acquire an inflammatory phenotype to accommodate immune cells in specific niches and to provide migration, differentiation, and growth factors. In the heart, balancing of fibroblast activity is critical for cardiac homeostasis and optimal organ function during inflammation. Fibroblasts sustain cardiac homeostasis by generating local niche environments that support housekeeping functions and by actively engaging in intercellular cross talk. During inflammatory perturbations, cardiac fibroblasts rapidly switch to an inflammatory state and actively communicate with infiltrating immune cells to orchestrate immune cell migration and activity. Here, we summarize the current knowledge on the molecular landscape of cardiac fibroblasts, focusing on their dual role in promoting tissue homeostasis and modulating immune cell-cardiomyocyte interaction. In addition, we discuss potential future avenues for manipulating cardiac fibroblast activity during myocardial inflammation., Competing Interests: Disclosures C. Perez-Shibayama, C. Gil-Cruz, and B. Ludewig are founders and C. Perez-Shibayama, C. Gil-Cruz, and B. Ludewig are shareholders of Stromal Therapeutics AG, Basel, Switzerland. B. Ludewig is a member of the board of Stromal Therapeutics AG, Basel, Switzerland. C. Perez-Shibayama, C. Gil-Cruz, and B. Ludewig are listed as inventors on patent WO 2022/084400 A1. The other author reports no conflicts.
- Published
- 2024
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5. Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis.
- Author
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Perez-Shibayama C, Gil-Cruz C, Cadosch N, Lütge M, Cheng HW, De Martin A, Frischmann K, Joachimbauer A, Onder L, Papadopoulou I, Papadopoulou C, Ring S, Krebs P, Vu VP, Nägele MP, Rossi VA, Parianos D, Zsilavecz VW, Cooper LT, Flammer A, Ruschitzka F, Rainer PP, Schmidt D, and Ludewig B
- Subjects
- Animals, Humans, Male, Signal Transduction, Mice, Cellular Microenvironment, Intercellular Signaling Peptides and Proteins metabolism, Intercellular Signaling Peptides and Proteins genetics, Female, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Mice, Inbred C57BL, Myocardium metabolism, Myocardium pathology, Myocardium immunology, Myocarditis metabolism, Myocarditis pathology, Myocarditis immunology, Fibrosis pathology, Fibrosis metabolism, Bone Morphogenetic Protein 4 metabolism, Bone Morphogenetic Protein 4 genetics, Disease Models, Animal, Autoimmune Diseases pathology, Autoimmune Diseases metabolism, Autoimmune Diseases immunology
- Abstract
Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4-gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure., (© 2024. The Author(s).)
- Published
- 2024
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6. Conserved stromal-immune cell circuits secure B cell homeostasis and function.
- Author
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Lütge M, De Martin A, Gil-Cruz C, Perez-Shibayama C, Stanossek Y, Onder L, Cheng HW, Kurz L, Cadosch N, Soneson C, Robinson MD, Stoeckli SJ, Ludewig B, and Pikor NB
- Subjects
- Mice, Humans, Animals, Immunity, Humoral, Dendritic Cells, Follicular, Homeostasis, B-Lymphocytes, Stromal Cells
- Abstract
B cell zone reticular cells (BRCs) form stable microenvironments that direct efficient humoral immunity with B cell priming and memory maintenance being orchestrated across lymphoid organs. However, a comprehensive understanding of systemic humoral immunity is hampered by the lack of knowledge of global BRC sustenance, function and major pathways controlling BRC-immune cell interactions. Here we dissected the BRC landscape and immune cell interactome in human and murine lymphoid organs. In addition to the major BRC subsets underpinning the follicle, including follicular dendritic cells, PI16
+ RCs were present across organs and species. As well as BRC-produced niche factors, immune cell-driven BRC differentiation and activation programs governed the convergence of shared BRC subsets, overwriting tissue-specific gene signatures. Our data reveal that a canonical set of immune cell-provided cues enforce bidirectional signaling programs that sustain functional BRC niches across lymphoid organs and species, thereby securing efficient humoral immunity., (© 2023. The Author(s).)- Published
- 2023
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7. Fibroblasts tune myocardial inflammation and remodeling.
- Author
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Perez-Shibayama C, Gil-Cruz C, and Ludewig B
- Published
- 2022
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8. Intestinal fibroblastic reticular cell niches control innate lymphoid cell homeostasis and function.
- Author
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Cheng HW, Mörbe U, Lütge M, Engetschwiler C, Onder L, Novkovic M, Gil-Cruz C, Perez-Shibayama C, Hehlgans T, Scandella E, and Ludewig B
- Subjects
- Fibroblasts, Homeostasis, Intestines, Immunity, Innate, Lymphocytes
- Abstract
Innate lymphoid cells (ILCs) govern immune cell homeostasis in the intestine and protect the host against microbial pathogens. Various cell-intrinsic pathways have been identified that determine ILC development and differentiation. However, the cellular components that regulate ILC sustenance and function in the intestinal lamina propria are less known. Using single-cell transcriptomic analysis of lamina propria fibroblasts, we identify fibroblastic reticular cells (FRCs) that underpin cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Genetic ablation of lymphotoxin-β receptor expression in Ccl19-expressing FRCs blocks the maturation of CPs into mature ILFs. Interactome analysis shows the major niche factors and processes underlying FRC-ILC crosstalk. In vivo validation confirms that a sustained lymphotoxin-driven feedforward loop of FRC activation including IL-7 generation is critical for the maintenance of functional ILC populations. In sum, our study indicates critical fibroblastic niches within the intestinal lamina propria that control ILC homeostasis and functionality and thereby secure protective gut immunity., (© 2022. The Author(s).)
- Published
- 2022
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9. Viral vector-mediated reprogramming of the fibroblastic tumor stroma sustains curative melanoma treatment.
- Author
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Ring SS, Cupovic J, Onder L, Lütge M, Perez-Shibayama C, Gil-Cruz C, Scandella E, De Martin A, Mörbe U, Hartmann F, Wenger R, Spiegl M, Besse A, Bonilla WV, Stemeseder F, Schmidt S, Orlinger KK, Krebs P, Ludewig B, and Flatz L
- Subjects
- Animals, Antigens, Neoplasm genetics, Antigens, Neoplasm immunology, Cancer Vaccines genetics, Cancer Vaccines immunology, Cancer-Associated Fibroblasts immunology, Cancer-Associated Fibroblasts pathology, Cellular Reprogramming Techniques methods, Chemokine CXCL13 genetics, Chemokine CXCL13 immunology, Female, Genetic Vectors, Interleukin-33 deficiency, Interleukin-33 genetics, Interleukin-33 immunology, Intramolecular Oxidoreductases genetics, Intramolecular Oxidoreductases immunology, Lymphocytic choriomeningitis virus genetics, Melanoma, Experimental immunology, Melanoma, Experimental pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Stromal Cells immunology, Stromal Cells pathology, T-Lymphocytes immunology, T-Lymphocytes pathology, Tumor Microenvironment immunology, Melanoma, Experimental therapy
- Abstract
The tumor microenvironment (TME) is a complex amalgam of tumor cells, immune cells, endothelial cells and fibroblastic stromal cells (FSC). Cancer-associated fibroblasts are generally seen as tumor-promoting entity. However, it is conceivable that particular FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector expressing a melanocyte differentiation antigen resulted in T cell-dependent long-term control of melanomas. Using single-cell RNA-seq analysis, we demonstrate that viral vector-mediated transduction reprogrammed and activated a Cxcl13-expressing FSC subset that show a pronounced immunostimulatory signature and increased expression of the inflammatory cytokine IL-33. Ablation of Il33 gene expression in Cxcl13-Cre-positive FSCs reduces the functionality of intratumoral T cells and unleashes tumor growth. Thus, reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment by locally sustaining the activity of tumor-specific T cells., (© 2021. The Author(s).)
- Published
- 2021
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10. Fibroblastic reticular cell lineage convergence in Peyer's patches governs intestinal immunity.
- Author
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Prados A, Onder L, Cheng HW, Mörbe U, Lütge M, Gil-Cruz C, Perez-Shibayama C, Koliaraki V, Ludewig B, and Kollias G
- Subjects
- Animals, Cell Communication, Cells, Cultured, Coronavirus Infections immunology, Coronavirus Infections metabolism, Coronavirus Infections virology, Disease Models, Animal, Fibroblasts metabolism, Gastrointestinal Microbiome, Gene Expression Profiling, Gene Expression Regulation, Developmental, Host-Pathogen Interactions, Intestinal Mucosa metabolism, Intestinal Mucosa microbiology, Intestinal Mucosa virology, Intestine, Small metabolism, Intestine, Small microbiology, Intestine, Small virology, Mice, Inbred C57BL, Mice, Knockout, Murine hepatitis virus immunology, Murine hepatitis virus pathogenicity, Peyer's Patches metabolism, Peyer's Patches microbiology, Peyer's Patches virology, Phenotype, Single-Cell Analysis, Transcriptome, Mice, Cell Lineage, Fibroblasts immunology, Immunity, Mucosal, Intestinal Mucosa immunology, Intestine, Small immunology, Peyer's Patches immunology
- Abstract
Fibroblastic reticular cells (FRCs) determine the organization of lymphoid organs and control immune cell interactions. While the cellular and molecular mechanisms underlying FRC differentiation in lymph nodes and the splenic white pulp have been elaborated to some extent, in Peyer's patches (PPs) they remain elusive. Using a combination of single-cell transcriptomics and cell fate mapping in advanced mouse models, we found that PP formation in the mouse embryo is initiated by an expansion of perivascular FRC precursors, followed by FRC differentiation from subepithelial progenitors. Single-cell transcriptomics and cell fate mapping confirmed the convergence of perivascular and subepithelial FRC lineages. Furthermore, lineage-specific loss- and gain-of-function approaches revealed that the two FRC lineages synergistically direct PP organization, maintain intestinal microbiome homeostasis and control anticoronavirus immune responses in the gut. Collectively, this study reveals a distinct mosaic patterning program that generates key stromal cell infrastructures for the control of intestinal immunity.
- Published
- 2021
- Full Text
- View/download PDF
11. Type I interferon signaling in fibroblastic reticular cells prevents exhaustive activation of antiviral CD8 + T cells.
- Author
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Perez-Shibayama C, Islander U, Lütge M, Cheng HW, Onder L, Ring SS, De Martin A, Novkovic M, Colston J, Gil-Cruz C, and Ludewig B
- Subjects
- Animals, Cell Line, Interferon-gamma immunology, Lymphocytic choriomeningitis virus, Mice, Inbred C57BL, Mice, Transgenic, Receptor, Interferon alpha-beta genetics, Receptor, Interferon alpha-beta immunology, Signal Transduction, Tumor Necrosis Factor-alpha immunology, CD8-Positive T-Lymphocytes immunology, Fibroblasts immunology, Interferon Type I immunology, Lymphocytic Choriomeningitis immunology, Stromal Cells immunology
- Abstract
Fibroblastic reticular cells (FRCs) are stromal cells that actively promote the induction of immune responses by coordinating the interaction of innate and adaptive immune cells. However, whether and to which extent immune cell activation is determined by lymph node FRC reprogramming during acute viral infection has remained unexplored. Here, we genetically ablated expression of the type I interferon-α receptor ( Ifnar ) in Ccl19-Cre
+ cells and found that sensing of type I interferon imprints an antiviral state in FRCs and thereby preserves myeloid cell composition in lymph nodes of naive mice. During localized lymphocytic choriomeningitis virus infection, IFNAR signaling precipitated profound phenotypic adaptation of all FRC subsets enhancing antigen presentation, chemokine-driven immune cell recruitment, and immune regulation. The IFNAR-dependent shift of all FRC subsets toward an immunostimulatory state reduced exhaustive CD8+ T cell activation. In sum, these results unveil intricate circuits underlying type I IFN sensing in lymph node FRCs that enable protective antiviral immunity., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2020
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12. Remodeling of light and dark zone follicular dendritic cells governs germinal center responses.
- Author
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Pikor NB, Mörbe U, Lütge M, Gil-Cruz C, Perez-Shibayama C, Novkovic M, Cheng HW, Nombela-Arrieta C, Nagasawa T, Linterman MA, Onder L, and Ludewig B
- Subjects
- Animals, B-Lymphocytes immunology, B-Lymphocytes metabolism, Biomarkers, Cell Communication, Chemokine CXCL12 metabolism, Mice, Mice, Transgenic, Phenotype, Single-Cell Analysis, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Darkness, Dendritic Cells, Follicular immunology, Dendritic Cells, Follicular metabolism, Germinal Center immunology, Germinal Center metabolism, Immunomodulation radiation effects, Light
- Abstract
Efficient generation of germinal center (GC) responses requires directed movement of B cells between distinct microenvironments underpinned by specialized B cell-interacting reticular cells (BRCs). How BRCs are reprogrammed to cater to the developing GC remains unclear, and studying this process is largely hindered by incomplete resolution of the cellular composition of the B cell follicle. Here we used genetic targeting of Cxcl13-expressing cells to define the molecular identity of the BRC landscape. Single-cell transcriptomic analysis revealed that BRC subset specification was predetermined in the primary B cell follicle. Further topological remodeling of light and dark zone follicular dendritic cells required CXCL12-dependent crosstalk with B cells and dictated GC output by retaining B cells in the follicle and steering their interaction with follicular helper T cells. Together, our results reveal that poised BRC-defined microenvironments establish a feed-forward system that determines the efficacy of the GC reaction.
- Published
- 2020
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13. Conservation of the OmpC Porin Among Typhoidal and Non-Typhoidal Salmonella Serovars.
- Author
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Valero-Pacheco N, Blight J, Aldapa-Vega G, Kemlo P, Pérez-Toledo M, Wong-Baeza I, Kurioka A, Perez-Shibayama C, Gil-Cruz C, Sánchez-Torres LE, Pastelin-Palacios R, Isibasi A, Reyes-Sandoval A, Klenerman P, and López-Macías C
- Subjects
- Amino Acid Sequence, Bacterial Proteins chemistry, Bacterial Proteins metabolism, Conserved Sequence, Humans, Phylogeny, Porins chemistry, Porins metabolism, Protein Conformation, alpha-Helical, Salmonella chemistry, Salmonella classification, Salmonella metabolism, Salmonella Infections microbiology, Salmonella typhi chemistry, Salmonella typhi classification, Salmonella typhi genetics, Salmonella typhi metabolism, Sequence Alignment, Typhoid Fever microbiology, Bacterial Proteins genetics, Porins genetics, Salmonella genetics
- Abstract
Salmonella enterica infections remain a challenging health issue, causing significant morbidity and mortality worldwide. Current vaccines against typhoid fever display moderate efficacy whilst no licensed vaccines are available for paratyphoid fever or invasive non-typhoidal salmonellosis. Therefore, there is an urgent need to develop high efficacy broad-spectrum vaccines that can protect against typhoidal and non-typhoidal Salmonella . The Salmonella outer membrane porins OmpC and OmpF, have been shown to be highly immunogenic antigens, efficiently eliciting protective antibody, and cellular immunity. Furthermore, enterobacterial porins, particularly the OmpC, have a high degree of homology in terms of sequence and structure, thus making them a suitable vaccine candidate. However, the degree of the amino acid conservation of OmpC among typhoidal and non-typhoidal Salmonella serovars is currently unknown. Here we used a bioinformatical analysis to classify the typhoidal and non-typhoidal Salmonella OmpC amino acid sequences into different clades independently of their serological classification. Further, our analysis determined that the porin OmpC contains various amino acid sequences that are highly conserved among both typhoidal and non-typhoidal Salmonella serovars. Critically, some of these highly conserved sequences were located in the transmembrane β-sheet within the porin β-barrel and have immunogenic potential for binding to MHC-II molecules, making them suitable candidates for a broad-spectrum Salmonella vaccine. Collectively, these findings suggest that these highly conserved sequences may be used for the rational design of an effective broad-spectrum vaccine against Salmonella ., (Copyright © 2020 Valero-Pacheco, Blight, Aldapa-Vega, Kemlo, Pérez-Toledo, Wong-Baeza, Kurioka, Perez-Shibayama, Gil-Cruz, Sánchez-Torres, Pastelin-Palacios, Isibasi, Reyes-Sandoval, Klenerman and López-Macías.)
- Published
- 2020
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14. Early-life programming of mesenteric lymph node stromal cell identity by the lymphotoxin pathway regulates adult mucosal immunity.
- Author
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Li C, Lam E, Perez-Shibayama C, Ward LA, Zhang J, Lee D, Nguyen A, Ahmed M, Brownlie E, Korneev KV, Rojas O, Sun T, Navarre W, He HH, Liao S, Martin A, Ludewig B, and Gommerman JL
- Subjects
- Animals, Feces microbiology, Female, Immunity, Mucosal, Lymph Nodes cytology, Lymphotoxin beta Receptor genetics, Lymphotoxin-alpha genetics, Male, Mesentery cytology, Mice, Inbred C57BL, Mice, Knockout, Immunoglobulin A immunology, Lymph Nodes immunology, Lymphotoxin beta Receptor immunology, Lymphotoxin-alpha immunology, Mesentery immunology, Stromal Cells immunology
- Abstract
Redundant mechanisms support immunoglobulin A (IgA) responses to intestinal antigens. These include multiple priming sites [mesenteric lymph nodes (MLNs), Peyer's patches, and isolated lymphoid follicles] and various cytokines that promote class switch to IgA, even in the absence of T cells. Despite these backup mechanisms, vaccination against enteric pathogens such as rotavirus has limited success in some populations. Genetic and environmental signals experienced during early life are known to influence mucosal immunity, yet the mechanisms for how these exposures operate remain unclear. Here, we used rotavirus infection to follow antigen-specific IgA responses through time and in different gut compartments. Using genetic and pharmacological approaches, we tested the role of the lymphotoxin (LT) pathway-known to support IgA responses-at different developmental stages. We found that LT-β receptor (LTβR) signaling in early life programs intestinal IgA responses in adulthood by affecting antibody class switch recombination to IgA and subsequent generation of IgA antibody-secreting cells within an intact MLN. In addition, early-life LTβR signaling dictates the phenotype and function of MLN stromal cells to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into how early-life LTβR signaling affects mucosal immune responses during adulthood., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2019
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15. Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy.
- Author
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Gil-Cruz C, Perez-Shibayama C, De Martin A, Ronchi F, van der Borght K, Niederer R, Onder L, Lütge M, Novkovic M, Nindl V, Ramos G, Arnoldini M, Slack EMC, Boivin-Jahns V, Jahns R, Wyss M, Mooser C, Lambrecht BN, Maeder MT, Rickli H, Flatz L, Eriksson U, Geuking MB, McCoy KD, and Ludewig B
- Subjects
- Animals, Autoimmune Diseases immunology, B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, Disease Models, Animal, Humans, Intestines microbiology, Mice, Mice, Inbred BALB C, Mice, Transgenic, Myocarditis immunology, Myosin Heavy Chains genetics, Myosin Heavy Chains immunology, Th17 Cells immunology, Autoimmune Diseases complications, Bacteroides immunology, Cardiomyopathy, Dilated immunology, Cardiomyopathy, Dilated microbiology, Gastrointestinal Microbiome immunology, Myocarditis complications, Peptides immunology, beta-Galactosidase immunology
- Abstract
Myocarditis can develop into inflammatory cardiomyopathy through chronic stimulation of myosin heavy chain 6-specific T helper (T
H )1 and TH 17 cells. However, mechanisms governing the cardiotoxicity programming of heart-specific T cells have remained elusive. Using a mouse model of spontaneous autoimmune myocarditis, we show that progression of myocarditis to lethal heart disease depends on cardiac myosin-specific TH 17 cells imprinted in the intestine by a commensal Bacteroides species peptide mimic. Both the successful prevention of lethal disease in mice by antibiotic therapy and the significantly elevated Bacteroides- specific CD4+ T cell and B cell responses observed in human myocarditis patients suggest that mimic peptides from commensal bacteria can promote inflammatory cardiomyopathy in genetically susceptible individuals. The ability to restrain cardiotoxic T cells through manipulation of the microbiome thereby transforms inflammatory cardiomyopathy into a targetable disease., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2019
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16. Divergent memory responses driven by adenoviral vectors are impacted by epitope competition.
- Author
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Colston JM, Hutchings C, Chinnakannan S, Highton A, Perez-Shibayama C, Ludewig B, and Klenerman P
- Subjects
- Adenoviridae immunology, Animals, Antigens, Viral immunology, CD8-Positive T-Lymphocytes immunology, Female, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus immunology, Mice, Mice, Inbred C57BL, Viral Proteins immunology, Epitopes, T-Lymphocyte immunology, Genetic Vectors immunology, Immunodominant Epitopes immunology, Immunologic Memory immunology
- Abstract
Adenoviral vectors induce robust epitope-specific CD8
+ T cell responses. Within the repertoire of responses generated both conventional memory evolution and the phenomenon of memory inflation are seen. The rules governing which epitopes inflate are not fully known, but may include a role for both antigen processing and competition. To investigate this, we looked at memory generated from vectors targeting the Gp33-41 (KAVYNFATC/K9C) epitope from the gp of lymphocytic choriomeningitis virus (LCMV) in mice. This well-described epitope has both the Gp33-41 and Gp34-41 epitopes embedded within it. Vaccination with a full-length gp or a minigene Ad-Gp33/K9C vector-induced conventional memory responses against the immunodominant Gp33/K9C epitope but a strong inflationary response against the Gp34/A8C epitope. These responses showed sustained in vivo function, with complete protection against LCMV infectious challenge. Given the unexpected competition between epitopes seen in the minigene model, we further tested epitope competition using the full-length Ad-LacZ (β-galactosidase) model. Generation of an Ad-LacZ vector with a single amino acid disruption of the inflationary β-gal96-103 /D8V epitope transformed the β-gal497-504 /I8V epitope from conventional to inflationary memory. This work collectively demonstrates the importance of epitope competition within adenoviral vector inserts and is of relevance to future studies using adenoviral vectored immunogens., (© 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2019
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17. Fibroblastic reticular cells at the nexus of innate and adaptive immune responses.
- Author
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Perez-Shibayama C, Gil-Cruz C, and Ludewig B
- Subjects
- Adaptive Immunity, Animals, Homeostasis, Humans, Immunity, Innate, Immunomodulation, Lymphocyte Activation, Adipose Tissue immunology, Fibroblasts immunology, Lymphoid Tissue immunology, Stromal Cells immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Lymphoid organs guarantee productive immune cell interactions through the establishment of distinct microenvironmental niches that are built by fibroblastic reticular cells (FRC). These specialized immune-interacting fibroblasts coordinate the migration and positioning of lymphoid and myeloid cells in lymphoid organs and provide essential survival and differentiation factors during homeostasis and immune activation. In this review, we will outline the current knowledge on FRC functions in secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches and will discuss how FRCs contribute to the regulation of immune processes in fat-associated lymphoid clusters. Moreover, recent evidence indicates that FRC critically impact immune regulatory processes, for example, through cytokine deprivation during immune activation or through fostering the induction of regulatory T cells. Finally, we highlight how different FRC subsets integrate innate immunological signals and molecular cues from immune cells to fulfill their function as nexus between innate and adaptive immune responses., (© 2019 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd.)
- Published
- 2019
- Full Text
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18. Fibroblastic reticular cells initiate immune responses in visceral adipose tissues and secure peritoneal immunity.
- Author
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Perez-Shibayama C, Gil-Cruz C, Cheng HW, Onder L, Printz A, Mörbe U, Novkovic M, Li C, Lopez-Macias C, Buechler MB, Turley SJ, Mack M, Soneson C, Robinson MD, Scandella E, Gommerman J, and Ludewig B
- Subjects
- Animals, Chemokine CCL2 immunology, Mice, Inbred C57BL, Mice, Transgenic, Monocytes immunology, Myeloid Differentiation Factor 88 immunology, Salmonella Infections immunology, Salmonella typhimurium, Tumor Necrosis Factor-alpha immunology, Fibroblasts cytology, Fibroblasts immunology, Intra-Abdominal Fat immunology, Peritoneal Cavity physiology
- Abstract
Immune protection of the body cavities depends on the swift activation of innate and adaptive immune responses in nonclassical secondary lymphoid organs known as fat-associated lymphoid clusters (FALCs). Compared with classical secondary lymphoid organs such as lymph nodes and Peyer's patches, FALCs develop along distinct differentiation trajectories and display a reduced structural complexity. Although it is well established that fibroblastic reticular cells (FRCs) are an integral component of the immune-stimulating infrastructure of classical secondary lymphoid organs, the role of FRCs in FALC-dependent peritoneal immunity remains unclear. Using FRC-specific gene targeting, we found that FRCs play an essential role in FALC-driven immune responses. Specifically, we report that initiation of peritoneal immunity was governed through FRC activation in a myeloid differentiation primary response 88 (MYD88)-dependent manner. FRC-specific ablation of MYD88 blocked recruitment of inflammatory monocytes into FALCs and subsequent CD4
+ T cell-dependent B-cell activation and IgG class switching. Moreover, containment of Salmonella infection was compromised in mice lacking MYD88 expression in FRCs, indicating that FRCs in FALCs function as an initial checkpoint in the orchestration of protective immune responses in the peritoneal cavity., (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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19. Evolution of Salmonella Typhi outer membrane protein-specific T and B cell responses in humans following oral Ty21a vaccination: A randomized clinical trial.
- Author
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Carreño JM, Perez-Shibayama C, Gil-Cruz C, Lopez-Macias C, Vernazza P, Ludewig B, and Albrich WC
- Subjects
- Administration, Oral, Antibodies, Bacterial immunology, Bacterial Vaccines administration & dosage, Humans, Salmonella typhi immunology, B-Lymphocytes immunology, Bacterial Outer Membrane Proteins immunology, Bacterial Vaccines immunology, CD4-Positive T-Lymphocytes immunology, Salmonella typhi metabolism
- Abstract
Vaccination against complex pathogens such as typhoidal and non-typhoidal Salmonella requires the concerted action of different immune effector mechanisms. Outer membrane proteins (Omps) of Salmonella Typhi are potent immunogens, which elicit long-lasting and protective immunity. Here, we followed the evolution of S. Typhi OmpC and F-specific T and B cell responses in healthy volunteers after vaccination with the vaccine strain Ty21a. To follow humoral and cellular immune responses, pre- and post-vaccination samples (PBMC, serum and stool) collected from 15 vaccinated and 5 non-vaccinated individuals. Immunoglobulin levels were assessed in peripheral blood by enzyme-linked immunosorbent assay. B cell and T cell activation were analyzed by flow cytometry. We observed a significant increase of circulating antibody-secreting cells and maximal Omp-specific serum IgG titers at day 25 post vaccination, while IgA titers in stool peaked at day 60. Likewise, Omp-specific CD4+ T cells in peripheral blood showed the highest expansion at day 60 post vaccination, concomitant with a significant increase in IFN-γ and TNFα production. These results indicate that S. Typhi Omp-specific B cell responses and polyfunctional CD4+ T cell responses evolve over a period of at least two months after application of the live attenuated vaccine. Moreover, these findings underscore the potential of S. Typhi Omps as subunit vaccine components., Trial Registration: ISRCTN18360696.
- Published
- 2017
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20. Salmonella Typhi Porins OmpC and OmpF Are Potent Adjuvants for T-Dependent and T-Independent Antigens.
- Author
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Pérez-Toledo M, Valero-Pacheco N, Pastelin-Palacios R, Gil-Cruz C, Perez-Shibayama C, Moreno-Eutimio MA, Becker I, Pérez-Tapia SM, Arriaga-Pizano L, Cunningham AF, Isibasi A, Bonifaz LC, and López-Macías C
- Abstract
Several microbial components, such as bacterial DNA and flagellin, have been used as experimental vaccine adjuvants because of their inherent capacity to efficiently activate innate immune responses. Likewise, our previous work has shown that the major Salmonella Typhi ( S . Typhi) outer membrane proteins OmpC and OmpF (porins) are highly immunogenic protective antigens that efficiently stimulate innate and adaptive immune responses in the absence of exogenous adjuvants. Moreover, S . Typhi porins induce the expression of costimulatory molecules on antigen-presenting cells through toll-like receptor canonical signaling pathways. However, the potential of major S . Typhi porins to be used as vaccine adjuvants remains unknown. Here, we evaluated the adjuvant properties of S . Typhi porins against a range of experimental and clinically relevant antigens. Co-immunization of S . Typhi porins with ovalbumin (OVA), an otherwise poorly immunogenic antigen, enhanced anti-OVA IgG titers, antibody class switching, and affinity maturation. This adjuvant effect was dependent on CD4
+ T-cell cooperation and was associated with an increase in IFN-γ, IL-17A, and IL-2 production by OVA-specific CD4+ T cells. Furthermore, co-immunization of S . Typhi porins with an inactivated H1N1 2009 pandemic influenza virus experimental vaccine elicited higher hemagglutinating anti-influenza IgG titers, antibody class switching, and affinity maturation. Unexpectedly, co-administration of S . Typhi porins with purified, unconjugated Vi capsular polysaccharide vaccine (Vi CPS)-a T-independent antigen-induced higher IgG antibody titers and class switching. Together, our results suggest that S . Typhi porins OmpC and OmpF are versatile vaccine adjuvants, which could be used to enhance T-cell immune responses toward a Th1/Th17 profile, while improving antibody responses to otherwise poorly immunogenic T-dependent and T-independent antigens.- Published
- 2017
- Full Text
- View/download PDF
21. Fibroblastic reticular cells regulate intestinal inflammation via IL-15-mediated control of group 1 ILCs.
- Author
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Gil-Cruz C, Perez-Shibayama C, Onder L, Chai Q, Cupovic J, Cheng HW, Novkovic M, Lang PA, Geuking MB, McCoy KD, Abe S, Cui G, Ikuta K, Scandella E, and Ludewig B
- Subjects
- Animals, Cells, Cultured, Immunity, Innate, Lymph Nodes pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 metabolism, Peyer's Patches pathology, Th1 Cells immunology, Toll-Like Receptor 7 genetics, Toll-Like Receptor 7 metabolism, Citrobacter rodentium immunology, Coronavirus Infections immunology, Enterobacteriaceae Infections immunology, Fibroblasts immunology, Interleukin-15 metabolism, Lymphocytes immunology, Murine hepatitis virus immunology
- Abstract
Fibroblastic reticular cells (FRCs) of secondary lymphoid organs form distinct niches for interaction with hematopoietic cells. We found here that production of the cytokine IL-15 by FRCs was essential for the maintenance of group 1 innate lymphoid cells (ILCs) in Peyer's patches and mesenteric lymph nodes. Moreover, FRC-specific ablation of the innate immunological sensing adaptor MyD88 unleashed IL-15 production by FRCs during infection with an enteropathogenic virus, which led to hyperactivation of group 1 ILCs and substantially altered the differentiation of helper T cells. Accelerated clearance of virus by group 1 ILCs precipitated severe intestinal inflammatory disease with commensal dysbiosis, loss of intestinal barrier function and diminished resistance to colonization. In sum, FRCs act as an 'on-demand' immunological 'rheostat' by restraining activation of group 1 ILCs and thereby preventing immunopathological damage in the intestine.
- Published
- 2016
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22. PLGA-microencapsulation protects Salmonella typhi outer membrane proteins from acidic degradation and increases their mucosal immunogenicity.
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Carreño JM, Perez-Shibayama C, Gil-Cruz C, Printz A, Pastelin R, Isibasi A, Chariatte D, Tanoue Y, Lopez-Macias C, Gander B, and Ludewig B
- Subjects
- Animals, Antibodies, Bacterial blood, Bacterial Outer Membrane Proteins chemistry, Lymph Nodes immunology, Mice, Inbred C57BL, Peyer's Patches immunology, Polylactic Acid-Polyglycolic Acid Copolymer, Protein Stability, Salmonella typhi, Typhoid-Paratyphoid Vaccines chemistry, Bacterial Outer Membrane Proteins immunology, Lactic Acid chemistry, Polyglycolic Acid chemistry, Typhoid-Paratyphoid Vaccines immunology
- Abstract
Salmonella (S.) enterica infections are an important global health problem with more than 20 million individuals suffering from enteric fever annually and more than 200,000 lethal cases per year. Although enteric fever can be treated appropriately with antibiotics, an increasing number of antibiotic resistant Salmonella strains is detected. While two vaccines against typhoid fever are currently on the market, their availability in subtropical endemic areas is limited because these products need to be kept in uninterrupted cold chains. Hence, the development of a thermally stable vaccine that induces mucosal immune responses would greatly improve human health in endemic areas. Here, we have combined the high structural stability of Salmonella typhi outer membrane proteins (porins) with their microencapsulation into poly(lactic-co-glycolic acid) (PLGA) to generate an orally applicable vaccine. Encapsulated porins were protected from acidic degradation and exhibited enhanced immunogenicity following oral administration. In particular, the vaccine elicited strong S. typhi-specific B cell responses in Peyer's patches and mesenteric lymph nodes. In sum, PLGA microencapsulation substantially improved the efficacy of oral vaccination against S. typhi., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
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23. Central Nervous System Stromal Cells Control Local CD8(+) T Cell Responses during Virus-Induced Neuroinflammation.
- Author
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Cupovic J, Onder L, Gil-Cruz C, Weiler E, Caviezel-Firner S, Perez-Shibayama C, Rülicke T, Bechmann I, and Ludewig B
- Subjects
- Animals, Cell Movement, Cellular Microenvironment, Central Nervous System virology, Chemokine CCL19 metabolism, Chemokine CCL21 metabolism, Endothelium, Vascular virology, Hepatitis A complications, Immunity, Cellular, Immunomodulation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Neurogenic Inflammation etiology, Receptors, CCR7 genetics, Stromal Cells virology, Viral Tropism, CD8-Positive T-Lymphocytes immunology, Central Nervous System immunology, Endothelium, Vascular immunology, Hepatitis A immunology, Hepatitis A virus immunology, Neurogenic Inflammation parasitology, Receptors, CCR7 metabolism, Stromal Cells immunology
- Abstract
Stromal cells generate a complex cellular scaffold that provides specialized microenvironments for lymphocyte activation in secondary lymphoid organs. Here, we assessed whether local activation of stromal cells in the central nervous system (CNS) is mandatory to transfer immune recognition from secondary lymphoid organs into the infected tissue. We report that neurotropic virus infection in mice triggered the establishment of such stromal cell niches in the CNS. CNS stromal cell activation was dominated by a rapid and vigorous production of CC-motif chemokine receptor (CCR) 7 ligands CCL19 and CCL21 by vascular endothelial cells and adjacent fibroblastic reticular cell (FRC)-like cells in the perivascular space. Moreover, CCR7 ligands produced by CNS stromal cells were crucial to support recruitment and local re-activation of antiviral CD8(+) T cells and to protect the host from lethal neuroinflammatory disease, indicating that CNS stromal cells generate confined microenvironments that control protective T cell immunity., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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24. Tuning up FALCs: immunological shielding in the body cavities.
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Perez-Shibayama C and Ludewig B
- Subjects
- Animals, Inflammation immunology, Intra-Abdominal Fat immunology, Lymphocytes immunology, Lymphoid Tissue immunology
- Published
- 2015
- Full Text
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25. Plasticity and complexity of B cell responses against persisting pathogens.
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Perez-Shibayama C, Gil-Cruz C, and Ludewig B
- Subjects
- Animals, Antibody Formation immunology, Germinal Center immunology, Germinal Center metabolism, Host-Parasite Interactions immunology, Humans, B-Lymphocytes physiology, Host-Pathogen Interactions immunology
- Abstract
Vaccines against acute infections execute their protective effects almost exclusively via the induction of antibodies. Development of protective vaccines against persisting pathogens lags behind probably because standard immunogens and application regimen do not sufficiently stimulate those circuits in B cell activation that mediate protection. In general, B cell responses against pathogen derived-antigens are generated through complex cellular interactions requiring the coordination of innate and adaptive immune mechanisms. In this review, we summarize recent findings from prototypic infection models to exemplify how generation of protective antibodies against persisting pathogens is imprinted by particular pathogen-derived factors and how distinct CD4(+) T cell populations determine the quality of these antibodies. Clearly, it is the high plasticity of these processes that is instrumental to drive tailored B cell responses that protect the host. In sum, application of novel knowledge on B cell plasticity and complexity can guide the development of rationally designed vaccines that elicit protective antibodies against persisting pathogens., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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26. IFN-γ-producing CD4+ T cells promote generation of protective germinal center-derived IgM+ B cell memory against Salmonella Typhi.
- Author
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Perez-Shibayama C, Gil-Cruz C, Pastelin-Palacios R, Cervantes-Barragan L, Hisaki E, Chai Q, Onder L, Scandella E, Regen T, Waisman A, Isibasi A, Lopez-Macias C, and Ludewig B
- Subjects
- Animals, CD4-Positive T-Lymphocytes pathology, Female, Germinal Center pathology, Humans, Interferon-gamma genetics, Male, Mice, Mice, Knockout, Salmonella Vaccines genetics, Salmonella Vaccines immunology, Typhoid Fever genetics, Typhoid Fever immunology, Typhoid Fever pathology, Typhoid Fever prevention & control, B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, Germinal Center immunology, Immunoglobulin M immunology, Immunologic Memory, Interferon-gamma immunology, Salmonella typhi immunology
- Abstract
Abs play a significant role in protection against the intracellular bacterium Salmonella Typhi. In this article, we investigated how long-term protective IgM responses can be elicited by a S. Typhi outer-membrane protein C- and F-based subunit vaccine (porins). We found that repeated Ag exposure promoted a CD4(+) T cell-dependent germinal center reaction that generated mutated IgM-producing B cells and was accompanied by a strong expansion of IFN-γ-secreting T follicular helper cells. Genetic ablation of individual cytokine receptors revealed that both IFN-γ and IL-17 are required for optimal germinal center reactions and production of porin-specific memory IgM(+) B cells. However, more profound reduction of porin-specific IgM B cell responses in the absence of IFN-γR signaling indicated that this cytokine plays a dominant role. Importantly, mutated IgM mAbs against porins exhibited bactericidal capacity and efficiently augmented S. Typhi clearance. In conclusion, repeated vaccination with S. Typhi porins programs type I T follicular helper cell responses that contribute to the diversification of B cell memory and promote the generation of protective IgM Abs., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2014
- Full Text
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27. Dendritic cell-specific delivery of Flt3L by coronavirus vectors secures induction of therapeutic antitumor immunity.
- Author
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Perez-Shibayama C, Gil-Cruz C, Nussbacher M, Allgäuer E, Cervantes-Barragan L, Züst R, and Ludewig B
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, Cancer Vaccines genetics, Cancer Vaccines immunology, Cell Line, Dendritic Cells immunology, Interleukin-15 genetics, Interleukin-15 immunology, Interleukin-2 genetics, Interleukin-2 immunology, Membrane Proteins immunology, Mice, Coronavirus genetics, Dendritic Cells metabolism, Genetic Vectors genetics, Immunotherapy methods, Membrane Proteins genetics, Neoplasms immunology, Neoplasms therapy
- Abstract
Efficacy of antitumor vaccination depends to a large extent on antigen targeting to dendritic cells (DCs). Here, we assessed antitumor immunity induced by attenuated coronavirus vectors which exclusively target DCs in vivo and express either lymphocyte- or DC-activating cytokines in combination with a GFP-tagged model antigen. Tracking of in vivo transduced DCs revealed that vectors encoding for Fms-like tyrosine kinase 3 ligand (Flt3L) exhibited a higher capacity to induce DC maturation compared to vectors delivering IL-2 or IL-15. Moreover, Flt3L vectors more efficiently induced tumor-specific CD8(+) T cells, expanded the epitope repertoire, and provided both prophylactic and therapeutic tumor immunity. In contrast, IL-2- or IL-15-encoding vectors showed a substantially lower efficacy in CD8(+) T cell priming and failed to protect the host once tumors had been established. Thus, specific in vivo targeting of DCs with coronavirus vectors in conjunction with appropriate conditioning of the microenvironment through Flt3L represents an efficient strategy for the generation of therapeutic antitumor immunity.
- Published
- 2013
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28. Salmonella Typhi OmpS1 and OmpS2 porins are potent protective immunogens with adjuvant properties.
- Author
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Moreno-Eutimio MA, Tenorio-Calvo A, Pastelin-Palacios R, Perez-Shibayama C, Gil-Cruz C, López-Santiago R, Baeza I, Fernández-Mora M, Bonifaz L, Isibasi A, Calva E, and López-Macías C
- Subjects
- Animals, Bacterial Outer Membrane Proteins administration & dosage, Bacterial Outer Membrane Proteins genetics, Dendritic Cells immunology, Dose-Response Relationship, Drug, Female, HEK293 Cells, Histocompatibility Antigens Class II metabolism, Humans, Immunization, Influenza A Virus, H1N1 Subtype immunology, Influenza Vaccines immunology, Interleukin-10 metabolism, Interleukin-6 metabolism, Lymphocyte Activation, Macrophages immunology, Mice, Mice, Inbred BALB C, Mice, Transgenic, Ovalbumin immunology, Polysaccharides, Bacterial immunology, Porins administration & dosage, Porins genetics, Salmonella Vaccines administration & dosage, Salmonella Vaccines genetics, Salmonella typhi genetics, T-Lymphocytes immunology, Time Factors, Toll-Like Receptor 2 agonists, Toll-Like Receptor 2 metabolism, Toll-Like Receptor 4 agonists, Toll-Like Receptor 4 metabolism, Transfection, Tumor Necrosis Factor-alpha metabolism, Typhoid Fever blood, Typhoid Fever immunology, Typhoid Fever microbiology, Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic genetics, Antibodies, Bacterial blood, Bacterial Outer Membrane Proteins immunology, Porins immunology, Salmonella Vaccines immunology, Salmonella typhi immunology, Typhoid Fever prevention & control
- Abstract
Salmonella enterica serovar Typhi (S. Typhi) is the causal agent of typhoid fever, a disease that primarily affects developing countries. Various antigens from this bacterium have been reported to be targets of the immune response. Recently, the S. Typhi genome has been shown to encode two porins--OmpS1 and OmpS2--which are expressed at low levels under in vitro culture conditions. In this study, we demonstrate that immunizing mice with either OmpS1 or OmpS2 induced production of specific, long-term antibody titres and conferred protection against S. Typhi challenge; in particular, OmpS1 was more immunogenic and conferred greater protective effects than OmpS2. We also found that OmpS1 is a Toll-like receptor 4 (TLR4) agonist, whereas OmpS2 is a TLR2 and TLR4 agonist. Both porins induced the production of tumour necrosis factor and interleukin-6, and OmpS2 was also able to induce interleukin-10 production. Furthermore, OmpS1 induced the over-expression of MHC II molecules in dendritic cells and OmpS2 induced the over-expression of CD40 molecules in macrophages and dendritic cells. Co-immunization of OmpS1 or OmpS2 with ovalbumin (OVA) increased anti-OVA antibody titres, the duration and isotype diversity of the OVA-specific antibody response, and the proliferation of T lymphocytes. These porins also had adjuvant effects on the antibody response when co-immunized with either the Vi capsular antigen from S. Typhi or inactivated 2009 pandemic influenza A(H1N1) virus [A(H1N1)pdm09]. Taken together, the data indicate that OmpS1 and OmpS2, despite being expressed at low levels under in vitro culture conditions, are potent protective immunogens with intrinsic adjuvant properties., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2013
- Full Text
- View/download PDF
29. Maturation of lymph node fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity.
- Author
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Chai Q, Onder L, Scandella E, Gil-Cruz C, Perez-Shibayama C, Cupovic J, Danuser R, Sparwasser T, Luther SA, Thiel V, Rülicke T, Stein JV, Hehlgans T, and Ludewig B
- Subjects
- Animals, Cell Differentiation, Cells, Cultured, Fibroblasts cytology, Fibroblasts immunology, Interleukin-7 biosynthesis, Lymph Nodes immunology, Lymphotoxin beta Receptor metabolism, Lymphotoxin-beta biosynthesis, Lymphotoxin-beta metabolism, Membrane Glycoproteins biosynthesis, Mesenchymal Stem Cells metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Murine hepatitis virus immunology, Myofibroblasts cytology, Signal Transduction, Coronavirus Infections immunology, Lymph Nodes cytology, Lymph Nodes metabolism, Myofibroblasts physiology, T-Lymphocytes immunology
- Abstract
The stromal scaffold of the lymph node (LN) paracortex is built by fibroblastic reticular cells (FRCs). Conditional ablation of lymphotoxin-β receptor (LTβR) expression in LN FRCs and their mesenchymal progenitors in developing LNs revealed that LTβR-signaling in these cells was not essential for the formation of LNs. Although T cell zone reticular cells had lost podoplanin expression, they still formed a functional conduit system and showed enhanced expression of myofibroblastic markers. However, essential immune functions of FRCs, including homeostatic chemokine and interleukin-7 expression, were impaired. These changes in T cell zone reticular cell function were associated with increased susceptibility to viral infection. Thus, myofibroblasic FRC precursors are able to generate the basic T cell zone infrastructure, whereas LTβR-dependent maturation of FRCs guarantees full immunocompetence and hence optimal LN function during infection., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
30. T helper cell- and CD40-dependent germline IgM prevents chronic virus-induced demyelinating disease.
- Author
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Gil-Cruz C, Perez-Shibayama C, Firner S, Waisman A, Bechmann I, Thiel V, Cervantes-Barragan L, and Ludewig B
- Subjects
- Analysis of Variance, Animals, B-Lymphocytes immunology, Central Nervous System immunology, Cytidine Deaminase deficiency, Demyelinating Diseases immunology, Enzyme-Linked Immunospot Assay, Flow Cytometry, Fluorescent Antibody Technique, Immunoglobulin M genetics, Mice, Mice, Knockout, CD40 Antigens immunology, Central Nervous System virology, Demyelinating Diseases virology, Immunoglobulin M immunology, Murine hepatitis virus immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
Generation of antiviral IgM is usually considered as a marker of a short-lived initial antibody response that is replaced by hypermutated and more-efficient IgG. However, once viruses have established a particular niche for their persistence (e.g., within the CNS), the immune system has to specifically mobilize a broad range of antimicrobial effectors to contain the pathogen in the long term. Infection of the CNS with the mouse hepatitis virus (MHV) provides a unique model situation in which the extent of inflammatory CNS disease is determined by the balance between antiviral immune control, viral replication, and immune-mediated damage. We show here that whereas antibody- or B cell-deficient mice failed to contain MHV CNS infection and developed progressive demyelinating disease, germline IgM produced in activation-induced cytidine deaminase-deficient mice (aicda(-/-)) provided long-term protection against the chronic multiple sclerosis-like disease. Furthermore, we found that appropriate B-cell activation within the CNS-draining lymph node and subsequent CXCR3-mediated migration of antiviral IgM-secreting cells to the infected CNS was dependent on CD40-mediated interaction of B cells with T helper cells. These data indicate that the CD40-mediated collaboration of T and B cells is critical to secure neuroprotective IgM responses during viral CNS infection.
- Published
- 2012
- Full Text
- View/download PDF
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