21 results on '"Schaeuble K"'
Search Results
2. Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma
- Author
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Bordry, N. Broggi, M.A.S. de Jonge, K. Schaeuble, K. Gannon, P.O. Foukas, P.G. Danenberg, E. Romano, E. Baumgaertner, P. Fankhauser, M. Wald, N. Cagnon, L. Abed-Maillard, S. Hajjami, H.M.-E. Murray, T. Ioannidou, K. Letovanec, I. Yan, P. Michielin, O. Matter, M. Swartz, M.A. Speiser, D.E.
- Abstract
Increased density of tumor-associated lymphatic vessels correlates with poor patient survival in melanoma and other cancers, yet lymphatic drainage is essential for initiating an immune response. Here we asked whether and how lymphatic vessel density (LVD) correlates with immune cell infiltration in primary tumors and lymph nodes (LNs) from patients with cutaneous melanoma. Using immunohistochemistry and quantitative image analysis, we found significant positive correlations between LVD and CD8+ T cell infiltration as well as expression of the immunosuppressive molecules inducible nitric oxide synthase (iNOS) and 2,3-dioxygénase (IDO). Interestingly, similar associations were seen in tumor-free LNs adjacent to metastatic ones, indicating loco-regional effects of tumors. Our data suggest that lymphatic vessels play multiple roles at tumor sites and LNs, promoting both T cell infiltration and adaptive immunosuppressive mechanisms. Lymph vessel associated T cell infiltration may increase immunotherapy success rates provided that the treatment overcomes adaptive immune resistance. © 2018, © 2018 The Author(s). Published with Taylor & Francis Group.
- Published
- 2018
3. CD4 + T cells in cancer.
- Author
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Speiser DE, Chijioke O, Schaeuble K, and Münz C
- Subjects
- Humans, Immunotherapy, CD4-Positive T-Lymphocytes, Tumor Microenvironment, CD8-Positive T-Lymphocytes, Neoplasms therapy
- Abstract
Cancer immunology and immunotherapy are driving forces of research and development in oncology, mostly focusing on CD8
+ T cells and the tumor microenvironment. Recent progress highlights the importance of CD4+ T cells, corresponding to the long-known fact that CD4+ T cells are central players and coordinators of innate and antigen-specific immune responses. Moreover, they have now been recognized as anti-tumor effector cells in their own right. Here we review the current status of CD4+ T cells in cancer, which hold great promise for improving knowledge and therapies in cancer., (© 2023. Springer Nature America, Inc.)- Published
- 2023
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4. Addendum: Mutually exclusive lymphangiogenesis or perineural infiltration in human skin squamous-cell carcinoma.
- Author
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Schaller J, Hajjami HM, Rusakiewicz S, Ioannidou K, Piazzon N, Miles A, Golshayan D, Gaide O, Hohl D, Speiser DE, and Schaeuble K
- Published
- 2022
- Full Text
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5. Gut microbiota severely hampers the efficacy of NAD-lowering therapy in leukemia.
- Author
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ElMokh O, Matsumoto S, Biniecka P, Bellotti A, Schaeuble K, Piacente F, Gallart-Ayala H, Ivanisevic J, Stamenkovic I, Nencioni A, Nahimana A, and Duchosal MA
- Subjects
- Cell Line, Tumor, Cytokines metabolism, Humans, NAD metabolism, Niacinamide pharmacology, Niacinamide therapeutic use, Nicotinamide Phosphoribosyltransferase metabolism, Gastrointestinal Microbiome, Leukemia, Neoplasms
- Abstract
Most cancer cells have high need for nicotinamide adenine dinucleotide (NAD
+ ) to sustain their survival. This led to the development of inhibitors of nicotinamide (NAM) phosphoribosyltransferase (NAMPT), the rate-limiting NAD+ biosynthesis enzyme from NAM. Such inhibitors kill cancer cells in preclinical studies but failed in clinical ones. To identify parameters that could negatively affect the therapeutic efficacy of NAMPT inhibitors and propose therapeutic strategies to circumvent such failure, we performed metabolomics analyses in tumor environment and explored the effect of the interaction between microbiota and cancer cells. Here we show that tumor environment enriched in vitamin B3 (NAM) or nicotinic acid (NA) significantly lowers the anti-tumor efficacy of APO866, a prototypic NAMPT inhibitor. Additionally, bacteria (from the gut, or in the medium) can convert NAM into NA and thus fuel an alternative NAD synthesis pathway through NA. This leads to the rescue from NAD depletion, prevents reactive oxygen species production, preserves mitochondrial integrity, blunts ATP depletion, and protects cancer cells from death.Our data in an in vivo preclinical model reveal that antibiotic therapy down-modulating gut microbiota can restore the anti-cancer efficacy of APO866. Alternatively, NAphosphoribosyltransferase inhibition may restore anti-cancer activity of NAMPT inhibitors in the presence of gut microbiota and of NAM in the diet., (© 2022. The Author(s).)- Published
- 2022
- Full Text
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6. Mutually exclusive lymphangiogenesis or perineural infiltration in human skin squamous-cell carcinoma.
- Author
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Schaller J, Hajjami HM, Rusakiewicz S, Ioannidou K, Piazzon N, Miles A, Golshayan D, Gaide O, Hohl D, Speiser DE, and Schaeuble K
- Abstract
Although tumor-associated lymphangiogenesis correlates with metastasis and poor prognosis in several cancers, it also supports T cell infiltration into the tumor and predicts favorable outcome to immunotherapy. The role of lymphatic vessels in skin squamous-cell carcinoma (sSCC), the second most common form of skin cancer, remains mostly unknown. Although anti-PD-1 therapy is beneficial for some patients with advanced sSCC, a greater understanding of disease mechanisms is still needed to develop better therapies. Using quantitative multiplex immunohistochemistry, we analyzed sSCC sections from 36 patients. CD8+ T cell infiltration showed great differences between patients, whereby these cells were mainly excluded from the tumor mass. Similar to our data in melanoma, sSCC with high density of lymphatic endothelial cells showed increased CD8+ T cell density in tumor areas. An entirely new observation is that sSCC with perineural infiltration but without metastasis was characterized by low lymphatic endothelial cell density. Since both, metastasis and perineural infiltration are known to affect tumor progression and patients' prognosis, it is important to identify the molecular drivers, opening future options for therapeutic targeting. Our data suggest that the mechanisms underlying perineural infiltration may be linked with the biology of lymphatic vessels and thus stroma., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2021 Schaller et al.)
- Published
- 2021
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7. Intratumoral CD8 + T cells with stem cell-like properties: Implications for cancer immunotherapy.
- Author
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Held W, Siddiqui I, Schaeuble K, and Speiser DE
- Subjects
- Hepatocyte Nuclear Factor 1-alpha metabolism, Humans, Neoplasms immunology, Neoplasms metabolism, Programmed Cell Death 1 Receptor metabolism, CD8-Positive T-Lymphocytes metabolism, Immunotherapy methods, Neoplasms therapy
- Abstract
Intratumoral PD-1
+ TCF1+ CD8+ T cells with stem cell-like properties mediate cellular expansion and tumor control in response to immunotherapy., (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
- Full Text
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8. Attenuation of chronic antiviral T-cell responses through constitutive COX2-dependent prostanoid synthesis by lymph node fibroblasts.
- Author
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Schaeuble K, Cannelle H, Favre S, Huang HY, Oberle SG, Speiser DE, Zehn D, and Luther SA
- Subjects
- Animals, Cell Line, Cell Movement genetics, Cell Movement immunology, Cell Proliferation genetics, Cyclooxygenase 2 genetics, Cyclooxygenase 2 metabolism, Fibroblasts metabolism, Fibroblasts virology, Lymph Nodes cytology, Lymph Nodes metabolism, Lymphocyte Activation immunology, Lymphocytic Choriomeningitis immunology, Lymphocytic Choriomeningitis metabolism, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus immunology, Lymphocytic choriomeningitis virus physiology, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Prostaglandins biosynthesis, T-Lymphocytes virology, Cyclooxygenase 2 immunology, Fibroblasts immunology, Lymph Nodes immunology, Prostaglandins immunology, T-Lymphocytes immunology
- Abstract
Lymphoid T-zone fibroblastic reticular cells (FRCs) actively promote T-cell trafficking, homeostasis, and expansion but can also attenuate excessive T-cell responses via inducible nitric oxide (NO) and constitutive prostanoid release. It remains unclear how these FRC-derived mediators dampen T-cell responses and whether this occurs in vivo. Here, we confirm that murine lymph node (LN) FRCs produce prostaglandin E2 (PGE2) in a cyclooxygenase-2 (COX2)-dependent and inflammation-independent fashion. We show that this COX2/PGE2 pathway is active during both strong and weak T-cell responses, in contrast to NO, which only comes into play during strong T-cell responses. During chronic infections in vivo, PGE2-receptor signaling in virus-specific cluster of differentiation (CD)8 cytotoxic T cells was shown by others to suppress T-cell survival and function. Using COX2flox/flox mice crossed to mice expressing Cre recombinase expression under control of the CC chemokine ligand (CCL19) promoter (CCL19cre), we now identify CCL19+ FRC as the critical source of this COX2-dependent suppressive factor, suggesting PGE2-expressing FRCs within lymphoid tissues are an interesting therapeutic target to improve T-cell-mediated pathogen control during chronic infection., Competing Interests: I have read the journal's policy, and the authors of this manuscript have no competing interests.
- Published
- 2019
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9. Intratumoral Tcf1 + PD-1 + CD8 + T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy.
- Author
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Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S, Pais Ferreira D, Carmona SJ, Scarpellino L, Gfeller D, Pradervand S, Luther SA, Speiser DE, and Held W
- Subjects
- Animals, CD8-Positive T-Lymphocytes drug effects, Cell Differentiation, Cell Proliferation, Hepatitis A Virus Cellular Receptor 2 antagonists & inhibitors, Hepatocyte Nuclear Factor 1-alpha genetics, Humans, Immunotherapy, Lymphocytes, Tumor-Infiltrating drug effects, Melanoma immunology, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Antibodies, Monoclonal therapeutic use, CD8-Positive T-Lymphocytes immunology, Hepatocyte Nuclear Factor 1-alpha metabolism, Lymphocytes, Tumor-Infiltrating immunology, Melanoma therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, Stem Cells immunology, T-Lymphocyte Subsets immunology
- Abstract
Checkpoint blockade mediates a proliferative response of tumor-infiltrating CD8
+ T lymphocytes (TILs). The origin of this response has remained elusive because chronic activation promotes terminal differentiation or exhaustion of tumor-specific T cells. Here we identified a subset of tumor-reactive TILs bearing hallmarks of exhausted cells and central memory cells, including expression of the checkpoint protein PD-1 and the transcription factor Tcf1. Tcf1+ PD-1+ TILs mediated the proliferative response to immunotherapy, generating both Tcf1+ PD-1+ and differentiated Tcf1- PD-1+ cells. Ablation of Tcf1+ PD-1+ TILs restricted responses to immunotherapy. Tcf1 was not required for the generation of Tcf1+ PD-1+ TILs but was essential for the stem-like functions of these cells. Human TCF1+ PD-1+ cells were detected among tumor-reactive CD8+ T cells in the blood of melanoma patients and among TILs of primary melanomas. Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2019
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10. Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis.
- Author
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Huang HY, Rivas-Caicedo A, Renevey F, Cannelle H, Peranzoni E, Scarpellino L, Hardie DL, Pommier A, Schaeuble K, Favre S, Vogt TK, Arenzana-Seisdedos F, Schneider P, Buckley CD, Donnadieu E, and Luther SA
- Subjects
- Animals, B-Cell Activating Factor immunology, Chemokine CXCL12 immunology, Interleukin-6 immunology, Lymph Nodes cytology, Male, Mice, Plasma Cells cytology, Stromal Cells cytology, Stromal Cells immunology, Antibody Formation, Homeostasis immunology, Lymph Nodes immunology, Plasma Cells immunology
- Abstract
Antibody-secreting plasma cells (PCs) arise rapidly during adaptive immunity to control infections. The early PCs are retained within the reactive lymphoid organ where their localization and homeostasis rely on extrinsic factors, presumably produced by local niche cells. While myeloid cells have been proposed to form those niches, the contribution by colocalizing stromal cells has remained unclear. Here, we characterized a subset of fibroblastic reticular cells (FRCs) that forms a dense meshwork throughout medullary cords of lymph nodes (LNs) where PCs reside. This medullary FRC type is shown to be anatomically, phenotypically, and functionally distinct from T zone FRCs, both in mice and humans. By using static and dynamic imaging approaches, we provide evidence that medullary FRCs are the main cell type in contact with PCs guiding them in their migration. Medullary FRCs also represent a major local source of the PC survival factors IL-6, BAFF, and CXCL12, besides also producing APRIL. In vitro, medullary FRCs alone or in combination with macrophages promote PC survival while other LN cell types do not have this property. Thus, we propose that this FRC subset, together with medullary macrophages, forms PC survival niches within the LN medulla, and thereby helps in promoting the rapid development of humoral immunity, which is critical in limiting early pathogen spread., Competing Interests: The authors declare no conflict of interest.
- Published
- 2018
- Full Text
- View/download PDF
11. Lymphatic vessel density is associated with CD8 + T cell infiltration and immunosuppressive factors in human melanoma.
- Author
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Bordry N, Broggi MAS, de Jonge K, Schaeuble K, Gannon PO, Foukas PG, Danenberg E, Romano E, Baumgaertner P, Fankhauser M, Wald N, Cagnon L, Abed-Maillard S, Maby-El Hajjami H, Murray T, Ioannidou K, Letovanec I, Yan P, Michielin O, Matter M, Swartz MA, and Speiser DE
- Abstract
Increased density of tumor-associated lymphatic vessels correlates with poor patient survival in melanoma and other cancers, yet lymphatic drainage is essential for initiating an immune response. Here we asked whether and how lymphatic vessel density (LVD) correlates with immune cell infiltration in primary tumors and lymph nodes (LNs) from patients with cutaneous melanoma. Using immunohistochemistry and quantitative image analysis, we found significant positive correlations between LVD and CD8
+ T cell infiltration as well as expression of the immunosuppressive molecules inducible nitric oxide synthase (iNOS) and 2,3-dioxygénase (IDO). Interestingly, similar associations were seen in tumor-free LNs adjacent to metastatic ones, indicating loco-regional effects of tumors. Our data suggest that lymphatic vessels play multiple roles at tumor sites and LNs, promoting both T cell infiltration and adaptive immunosuppressive mechanisms. Lymph vessel associated T cell infiltration may increase immunotherapy success rates provided that the treatment overcomes adaptive immune resistance.- Published
- 2018
- Full Text
- View/download PDF
12. Perivascular Fibroblasts of the Developing Spleen Act as LTα1β2-Dependent Precursors of Both T and B Zone Organizer Cells.
- Author
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Schaeuble K, Britschgi MR, Scarpellino L, Favre S, Xu Y, Koroleva E, Lissandrin TKA, Link A, Matloubian M, Ware CF, Nedospasov SA, Tumanov AV, Cyster JG, and Luther SA
- Subjects
- Animals, Chemokine CCL19 metabolism, Chemokine CXCL13 metabolism, Chemokines, CXC metabolism, Lymphotoxin-alpha metabolism, Mice, Spleen cytology, Spleen metabolism, Cell Differentiation physiology, Fibroblasts metabolism, Fibroblasts physiology
- Abstract
T and B cell compartmentalization is a hallmark of secondary lymphoid organs and is maintained by chemokine-expressing stromal cells. How this stromal cell network initially develops and differentiates into two distinct subsets is poorly known, especially for the splenic white pulp (WP). Here, we show that perivascular fibroblast precursors are triggered by LTα1β2 signals to expand, express CCL19/21, and then differentiate into two functionally distinct fibroblast subsets responsible for B and T cell clustering and WP compartmentalization. Failure to express or sense CCL19 leads to impaired T zone development, while lack of B cells or LTα1β2 leads to an earlier and stronger impairment in WP development. We therefore propose that WP development proceeds in multiple steps, with LTα1β2
+ B cells acting as major inducer cells driving the expansion and gradual differentiation of perivascular fibroblasts into T and B zone organizer cells., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2017
- Full Text
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13. Essential role of CCL21 in establishment of central self-tolerance in T cells.
- Author
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Kozai M, Kubo Y, Katakai T, Kondo H, Kiyonari H, Schaeuble K, Luther SA, Ishimaru N, Ohigashi I, and Takahama Y
- Subjects
- Animals, Autoimmune Diseases genetics, Autoimmune Diseases immunology, Autoimmune Diseases metabolism, Central Tolerance genetics, Chemokine CCL21 genetics, Chemokine CCL21 metabolism, Dacryocystitis genetics, Dacryocystitis immunology, Dacryocystitis metabolism, Flow Cytometry, Gene Expression immunology, Lymph Nodes immunology, Lymph Nodes metabolism, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Mice, Transgenic, Microscopy, Confocal, Receptors, CCR7 immunology, Receptors, CCR7 metabolism, Reverse Transcriptase Polymerase Chain Reaction, Self Tolerance genetics, T-Lymphocytes metabolism, Thymocytes immunology, Thymocytes metabolism, Thymus Gland immunology, Thymus Gland metabolism, Central Tolerance immunology, Chemokine CCL21 immunology, Self Tolerance immunology, T-Lymphocytes immunology
- Abstract
The chemokine receptor CCR7 directs T cell relocation into and within lymphoid organs, including the migration of developing thymocytes into the thymic medulla. However, how three functional CCR7 ligands in mouse, CCL19, CCL21Ser, and CCL21Leu, divide their roles in immune organs is unclear. By producing mice specifically deficient in CCL21Ser, we show that CCL21Ser is essential for the accumulation of positively selected thymocytes in the thymic medulla. CCL21Ser-deficient mice were impaired in the medullary deletion of self-reactive thymocytes and developed autoimmune dacryoadenitis. T cell accumulation in the lymph nodes was also defective. These results indicate a nonredundant role of CCL21Ser in the establishment of self-tolerance in T cells in the thymic medulla, and reveal a functional inequality among CCR7 ligands in vivo., (© 2017 Kozai et al.)
- Published
- 2017
- Full Text
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14. Inflammation-Induced CCR7 Oligomers Form Scaffolds to Integrate Distinct Signaling Pathways for Efficient Cell Migration.
- Author
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Hauser MA, Schaeuble K, Kindinger I, Impellizzieri D, Krueger WA, Hauck CR, Boyman O, and Legler DF
- Subjects
- Dendritic Cells immunology, Dendritic Cells metabolism, Flow Cytometry, Fluorescence Resonance Energy Transfer, HEK293 Cells, Humans, Immunoprecipitation, Inflammation metabolism, Leukocytes, Mononuclear metabolism, Microscopy, Fluorescence, Real-Time Polymerase Chain Reaction, Receptors, CCR7 metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transfection, Chemotaxis immunology, Inflammation immunology, Leukocytes, Mononuclear immunology, Receptors, CCR7 immunology, Signal Transduction immunology
- Abstract
Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and T cell subpopulations to process guidance cues not only through classical G protein-dependent signaling but also by integrating an oligomer-dependent Src kinase signaling pathway. Efficient CCR7-driven migration depends on a hydrophobic oligomerization interface near the conserved NPXXY motif of G protein-coupled receptors as shown by mutagenesis screen and a CCR7-SNP demonstrating super-oligomer characteristics leading to enhanced Src activity and superior chemotaxis. Furthermore, Src phosphorylates oligomeric CCR7, thereby creating a docking site for SH2-domain-bearing signaling molecules. Finally, we identified CCL21-biased signaling that involved the phosphatase SHP2 to control efficient cell migration. Collectively, our data showed that CCR7 oligomers serve as molecular hubs regulating distinct signaling pathways., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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15. Ubiquitylation of the chemokine receptor CCR7 enables efficient receptor recycling and cell migration.
- Author
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Schaeuble K, Hauser MA, Rippl AV, Bruderer R, Otero C, Groettrup M, and Legler DF
- Subjects
- Animals, Cell Membrane drug effects, Cell Membrane metabolism, Chemokines pharmacology, Enzyme Activation drug effects, Extracellular Signal-Regulated MAP Kinases metabolism, HEK293 Cells, Humans, Lysine metabolism, Lysosomes drug effects, Lysosomes metabolism, Mice, Mutant Proteins metabolism, Phosphorylation drug effects, Precursor Cells, B-Lymphoid cytology, Precursor Cells, B-Lymphoid drug effects, Precursor Cells, B-Lymphoid metabolism, Protein Sorting Signals, Protein Transport drug effects, Ubiquitination drug effects, trans-Golgi Network drug effects, trans-Golgi Network metabolism, Cell Movement drug effects, Endocytosis drug effects, Receptors, CCR7 metabolism
- Abstract
The chemokine receptor CCR7 is essential for lymphocyte and dendritic cell homing to secondary lymphoid organs. Owing to the ability to induce directional migration, CCR7 and its ligands CCL19 and CCL21 are pivotal for the regulation of the immune system. Here, we identify a novel function for receptor ubiquitylation in the regulation of the trafficking process of this G-protein-coupled seven transmembrane receptor. We discovered that CCR7 is ubiquitylated in a constitutive, ligand-independent manner and that receptor ubiquitylation regulates the basal trafficking of CCR7 in the absence of chemokine. Upon CCL19 binding, we show that internalized CCR7 recycles back to the plasma membrane via the trans-Golgi network. An ubiquitylation-deficient CCR7 mutant internalized normally after ligand binding, but inefficiently recycled in immune cells and was transiently retarded in the trans-Golgi network compartment of HEK293 transfectants. Finally, we demonstrate that the lack of CCR7 ubiquitylation profoundly impairs immune cell migration. Our results provide evidence for a novel function of receptor ubiquitylation in the regulation of CCR7 recycling and immune cell migration.
- Published
- 2012
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16. Cross-talk between TCR and CCR7 signaling sets a temporal threshold for enhanced T lymphocyte migration.
- Author
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Schaeuble K, Hauser MA, Singer E, Groettrup M, and Legler DF
- Subjects
- Blotting, Western, Cell Separation, Flow Cytometry, Humans, Lymphocyte Activation immunology, Receptors, Antigen, T-Cell immunology, Receptors, CCR7 immunology, T-Lymphocytes cytology, T-Lymphocytes immunology, Chemotaxis, Leukocyte immunology, Receptor Cross-Talk immunology, Receptors, Antigen, T-Cell metabolism, Receptors, CCR7 metabolism, Signal Transduction immunology, T-Lymphocytes metabolism
- Abstract
Lymphocyte homing to, and motility within, lymph nodes is regulated by the chemokine receptor CCR7 and its two ligands CCL19 and CCL21. There, lymphocytes are exposed to a number of extracellular stimuli that influence cellular functions and determine the cell fate. In this study, we assessed the effect of TCR engagement on CCR7-mediated cell migration. We found that long-term TCR triggering of freshly isolated human T cells through CD3/CD28 attenuated CCR7-driven chemotaxis, whereas short-term activation significantly enhanced CCR7-mediated, but not CXCR4-mediated, migration efficiency. Short-term activation most prominently enhanced the migratory response of naive T cells of both CD4 and CD8 subsets. We identified distinct roles for Src family kinases in modulating CCR7-mediated T cell migration. We provide evidence that Fyn, together with Ca(2+)-independent protein kinase C isoforms, kept the migratory response of naive T cells toward CCL21 at a low level. In nonactivated T cells, CCR7 triggering induced a Fyn-dependent phosphorylation of the inhibitory Tyr505 of Lck. Inhibiting Fyn in these nonactivated T cells prevented the negative regulation of Lck and facilitated high CCR7-driven T cell chemotaxis. Moreover, we found that the enhanced migration of short-term activated T cells was accompanied by a synergistic, Src-dependent activation of the adaptor molecule linker for activation of T cells. Collectively, we characterize a cross-talk between the TCR and CCR7 and provide mechanistic evidence that the activation status of T cells controls lymphocyte motility and sets a threshold for their migratory response.
- Published
- 2011
- Full Text
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17. Adolescents' preferences for primary care provider interactions.
- Author
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Schaeuble K, Haglund K, and Vukovich M
- Subjects
- Adolescent, Clinical Nursing Research, Communication, Female, Focus Groups, Health Services Accessibility organization & administration, Humans, Male, Quality of Health Care, Young Adult, Adolescent Medicine organization & administration, Patient Preference, Physician-Patient Relations, Primary Health Care organization & administration
- Abstract
Purpose: Adolescents receive less primary care than other age groups. One reason may be the negative ways that providers sometimes interact with adolescents. The purpose was to develop knowledge regarding adolescents' preferences for provider interactions., Design and Methods: Design was descriptive and mixed method. Donabedian's healthcare quality model guided the study. Data were collected via focus groups and a survey., Results: Twenty-four adolescents participated. Four themes described their preferences: forming a relationship, supporting independence, assuring confidentiality, and conveying caring., Practice Implications: Care that is congruent with adolescents' preferences may improve quality of, and access to, care and, ultimately, health outcomes.
- Published
- 2010
- Full Text
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18. Distinct motifs in the chemokine receptor CCR7 regulate signal transduction, receptor trafficking and chemotaxis.
- Author
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Otero C, Eisele PS, Schaeuble K, Groettrup M, and Legler DF
- Subjects
- Amino Acid Motifs physiology, Animals, Calcium Signaling physiology, Cell Membrane metabolism, Cells, Cultured, Chemokine CCL19 metabolism, GTP-Binding Proteins metabolism, Humans, Mice, Mitogen-Activated Protein Kinase 3 metabolism, Models, Biological, Mutant Proteins metabolism, Protein Binding, Protein Transport physiology, Signal Transduction physiology, Chemotaxis physiology, Receptors, CCR7 chemistry, Receptors, CCR7 metabolism, Receptors, CCR7 physiology
- Abstract
The chemokine receptor CCR7, together with its ligands CCL19 and CCL21, is responsible for the correct homing and trafficking of dendritic cells and lymphocytes to secondary lymphoid tissues. Moreover, cancer cells can utilize CCR7 to metastasize to draining lymph nodes. However, information on CCR7 signaling leading to cell migration or receptor trafficking is sparse. Using novel CCR7 deletion mutants with successive truncations of the intracellular C-terminus and a mutant with impaired G-protein coupling, we identified distinct motifs responsible for various aspects of CCR7 signal transduction. Deleting a Ser/Thr motif at the tip of the intracellular tail of CCR7 resulted in an impaired chemokine-mediated activation of Erk1/2 kinases. Interestingly, deleting an additional adjacent motif restored the ability of CCL19-mediated Erk1/2 phosphorylation, suggesting the presence of a regulatory motif. Both the Ser/Thr and the regulatory motif are dispensable for signaling events leading to cell migration and receptor trafficking. A CCR7 mutant lacking virtually the complete C-terminus readily bound CCL19 and was internalized, but was unable to activate the G protein and to transmit signals required for cell migration, mobilization of [Ca2+](i) and Erk1/2 activation. Finally, G-protein coupling was critical for [Ca2+](i) mobilization, Erk1/2 phosphorylation and chemotaxis, but not for CCR7 trafficking.
- Published
- 2008
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19. Commuting (to) suicide: an update on nucleocytoplasmic transport in apoptosis.
- Author
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Grote P, Schaeuble K, and Ferrando-May E
- Subjects
- Animals, Humans, Models, Biological, Oxidation-Reduction, Reactive Oxygen Species, Active Transport, Cell Nucleus physiology, Apoptosis physiology, Apoptosis Regulatory Proteins metabolism, Caspases metabolism, Nucleocytoplasmic Transport Proteins metabolism, Oxidative Stress physiology
- Abstract
Commuting is the process of travelling between a place of residence and a place of work. In the context of biology, this expression evokes the continuous movement of macromolecules between different compartments of a eukaryotic cell. Transport in and out of the nucleus is a major example of intracellular commuting. This article discusses recent findings that substantiate the emerging link between nucleocytoplasmic transport and the signalling and execution of cell death.
- Published
- 2007
- Full Text
- View/download PDF
20. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence.
- Author
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Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, Wappler I, Birket MJ, Harold G, Schaeuble K, Birch-Machin MA, Kirkwood TB, and von Zglinicki T
- Subjects
- Age Factors, Calcium metabolism, Cell Line, Fibroblasts, Flow Cytometry, Humans, In Situ Hybridization, Fluorescence, Microscopy, Electron, Transmission, Mitochondria metabolism, Mitochondria ultrastructure, RNA, Small Interfering genetics, Stochastic Processes, Cellular Senescence physiology, Mitochondria physiology, Reactive Oxygen Species metabolism, Telomere physiology
- Abstract
Aging is an inherently stochastic process, and its hallmark is heterogeneity between organisms, cell types, and clonal populations, even in identical environments. The replicative lifespan of primary human cells is telomere dependent; however, its heterogeneity is not understood. We show that mitochondrial superoxide production increases with replicative age in human fibroblasts despite an adaptive UCP-2-dependent mitochondrial uncoupling. This mitochondrial dysfunction is accompanied by compromised [Ca(2+)]i homeostasis and other indicators of a retrograde response in senescent cells. Replicative senescence of human fibroblasts is delayed by mild mitochondrial uncoupling. Uncoupling reduces mitochondrial superoxide generation, slows down telomere shortening, and delays formation of telomeric gamma-H2A.X foci. This indicates mitochondrial production of reactive oxygen species (ROS) as one of the causes of replicative senescence. By sorting early senescent (SES) cells from young proliferating fibroblast cultures, we show that SES cells have higher ROS levels, dysfunctional mitochondria, shorter telomeres, and telomeric gamma-H2A.X foci. We propose that mitochondrial ROS is a major determinant of telomere-dependent senescence at the single-cell level that is responsible for cell-to-cell variation in replicative lifespan.
- Published
- 2007
- Full Text
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21. Role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase (ALDH-2) activity. Implications for mitochondrial oxidative stress and nitrate tolerance.
- Author
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Wenzel P, Hink U, Oelze M, Schuppan S, Schaeuble K, Schildknecht S, Ho KK, Weiner H, Bachschmid M, Münzel T, and Daiber A
- Subjects
- Aldehyde Dehydrogenase chemistry, Aldehyde Dehydrogenase, Mitochondrial, Animals, Glutathione chemistry, Glutathione metabolism, Inhibitory Concentration 50, Male, Mitochondrial Proteins chemistry, Models, Biological, Myocardium metabolism, Oxidants chemistry, Oxidants metabolism, Rats, Rats, Wistar, Aldehyde Dehydrogenase physiology, Mitochondria metabolism, Mitochondrial Proteins physiology, Nitrates chemistry, Oxidation-Reduction, Oxidative Stress, Thioctic Acid chemistry
- Abstract
Chronic therapy with nitroglycerin results in a rapid development of nitrate tolerance, which is associated with an increased production of reactive oxygen species. We have recently shown that mitochondria are an important source of nitroglycerin-induced oxidants and that the nitroglycerin-bioactivating mitochondrial aldehyde dehydrogenase is oxidatively inactivated in the setting of tolerance. Here we investigated the effect of various oxidants on aldehyde dehydrogenase activity and its restoration by dihydrolipoic acid. In vivo tolerance in Wistar rats was induced by infusion of nitroglycerin (6.6 microg/kg/min, 4 days). Vascular reactivity was measured by isometric tension studies of isolated aortic rings in response to nitroglycerin. Chronic nitroglycerin infusion lead to impaired vascular responses to nitroglycerin and decreased dehydrogenase activity, which was corrected by dihydrolipoic acid co-incubation. Superoxide, peroxynitrite, and nitroglycerin itself were highly efficient in inhibiting mitochondrial and yeast aldehyde dehydrogenase activity, which was restored by dithiol compounds such as dihydrolipoic acid and dithiothreitol. Hydrogen peroxide and nitric oxide were rather insensitive inhibitors. Our observations indicate that mitochondrial oxidative stress (especially superoxide and peroxynitrite) in response to organic nitrate treatment may inactivate aldehyde dehydrogenase thereby leading to nitrate tolerance. Glutathionylation obviously amplifies oxidative inactivation of the enzyme providing another regulatory pathway. Furthermore, the present data demonstrate that the mitochondrial dithiol compound dihydrolipoic acid restores mitochondrial aldehyde dehydrogenase activity via reduction of a disulfide at the active site and thereby improves nitrate tolerance.
- Published
- 2007
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