48 results on '"Barthlott T"'
Search Results
2. Das B-Zell-System
- Author
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Holländer, G.A., primary, Barthlott, T., additional, Keller, M.P., additional, Krenger, W., additional, and Piali, L., additional
- Published
- 2005
- Full Text
- View/download PDF
3. Periphere lymphatische Organe
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Holländer, G.A., primary, Barthlott, T., additional, Keller, M.P., additional, Krenger, W., additional, and Piali, L., additional
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- 2005
- Full Text
- View/download PDF
4. T-Zell-System
- Author
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Holländer, G.A., primary, Barthlott, T., additional, Keller, M.P., additional, Krenger, W., additional, and Piali, L., additional
- Published
- 2005
- Full Text
- View/download PDF
5. Übersicht
- Author
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Holländer, G.A., primary, Barthlott, T., additional, Keller, M.P., additional, Krenger, W., additional, and Piali, L., additional
- Published
- 2005
- Full Text
- View/download PDF
6. Das Komplementsystem
- Author
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Holländer, G.A., primary, Barthlott, T., additional, Keller, M.P., additional, Krenger, W., additional, and Piali, L., additional
- Published
- 2005
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- View/download PDF
7. Spezielle Aspekte des Immunsystems
- Author
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Holländer, G.A., primary, Barthlott, T., additional, Keller, M.P., additional, Krenger, W., additional, and Piali, L., additional
- Published
- 2005
- Full Text
- View/download PDF
8. Der programmierte Zelltod
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Holländer, G.A., primary, Barthlott, T., additional, Keller, M.P., additional, Krenger, W., additional, and Piali, L., additional
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- 2005
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- View/download PDF
9. Zytokine und ihre Netzwerke
- Author
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Holländer, G.A., primary, Barthlott, T., additional, Keller, M.P., additional, Krenger, W., additional, and Piali, L., additional
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- 2005
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10. MHC-Moleküle und Antigenpräsentation
- Author
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Holländer, G.A., primary, Barthlott, T., additional, Keller, M.P., additional, Krenger, W., additional, and Piali, L., additional
- Published
- 2005
- Full Text
- View/download PDF
11. Leukozyten-Migration
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Holländer, G.A., primary, Barthlott, T., additional, Keller, M.P., additional, Krenger, W., additional, and Piali, L., additional
- Published
- 2005
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12. Das natürliche Immunsystem
- Author
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Holländer, G.A., primary, Barthlott, T., additional, Keller, M.P., additional, Krenger, W., additional, and Piali, L., additional
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- 2005
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13. CD25+CD4+ T cells compete with naïve CD4 T cells for interleukin 2 and exploit it for the induction of IL-10 production: 9.4
- Author
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Moncrieffe, H., Barthlott, T., Veldhoen, M., and Stockinger, B.
- Published
- 2004
14. The concept of space and competition in immune regulation: IS32
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Stockinger, B., Kassiotis, G., Barthlott, T., Moncrieffe, H., Veldhoen, M., and Bourgeois, C.
- Published
- 2004
15. Foxn1 regulates in postnatal thymic epithelial cells key target genes essential for T cell development
- Author
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Žuklys, S, Handel, A, Zhanybekova, S, Govani, F, Keller, M, Maio, S, Mayer, C, Teh, H, Hafen, K, Gallone, G, Barthlott, T, Ponting, C, and Hollander, G
- Subjects
integumentary system - Abstract
Thymic epithelial cell differentiation, growth and function depend on the expression of the transcription factor Foxn1, however its target genes have never been physically identified. Using novel static and inducible genetic model systems and chromatin studies, we provide now a genome wide map of direct Foxn1 target genes for postnatal thymic epithelia and define the Foxn1 binding motif. We detail the function of Foxn1 in these cells and demonstrate that in addition to the transcriptional control of genes involved in the attraction and lineage commitment of T cell precursors, Foxn1 regulates the expression of genes involved in antigen processing and thymocyte selection. Thus, critical events in thymic lympho-stromal cross-talk and T cell selection are indispensably choreographed by Foxn1.
- Published
- 2016
16. LENTIVIRAL TRANSDUCTION OF PRIMARY ADULT MOUSE THYMIC EPITHELIAL CELLS TO CREATE CELLS COMPETENT TO SUPPORT REGULAR THYMOPOIESIS BOTH IN VITRO AND IN VIVO
- Author
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Bosticardo, M, Beilin, C, Lombardo, A, Sergi, LS, Barthlott, T, Naldini, L, Villa, A, and Hollander, GA
- Published
- 2016
17. Lentiviral Vector-Mediated Induction of Oct4 Expression in Primary Adult Mouse Thymic Epithelial Cells To Generate Tools for Gene Replacement and Tissue Regeneration
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Bosticardo, M, Catucci, M, Beilin, C, Bortolomai, I, Lombardo, A, Sergi, L, Barthlott, T, Naldini, L, Villa, A, and Hollander, G
- Published
- 2014
18. Normal Thymic Selection of TCR Transgenic CD4 T Cells, but Impaired Survival in the Periphery Despite the Presence of Selecting MHC Molecules
- Author
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Barthlott T, Rj, Wright, and Brigitta Stockinger
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CD4-Positive T-Lymphocytes ,Mice ,Cell Survival ,Immunology ,Histocompatibility Antigens Class II ,Receptors, Antigen, T-Cell ,Animals ,Immunology and Allergy ,Cell Differentiation ,Thymus Gland - Abstract
In this paper, we investigate selection in the thymus and survival in the periphery of CD4 T cells, which carry a major histocompatibility class II-restricted transgenic TCR (A18 TCRtg) specific for a natural self Ag, the fifth component of complement (C5). A18 TCRtg thymocytes develop normal numbers of CD4 single-positive (SP) thymocytes, but do not show pronounced overselection as do some other TCR transgenic strains. CD4 SP cells are mature as judged by termination of CD8 synthesis, resistance to cortisone, and functional competence. The kinetics of positive selection, determined by BrdU labeling, are very fast. CD4 SP thymocytes are demonstrable within 2 days of labeling, and within 8 days after labeling a large proportion (20%) of lymph node T cells are recent thymic emigrants. The high number of recent thymic emigrants suggests rapid turnover of CD4 T cells in the periphery, which was confirmed by thymectomy and determination of CD4 T cell life spans. A18 TCRtg T cells have a t1/2 of ∼6 wk, despite the presence of selecting MHC molecules. This explains the failure to accumulate high numbers of peripheral T cells and suggests that the MHC-bound ligand(s) responsible for initiating survival signals is limiting for the selection and maintenance of A18 transgenic CD4 T cells.
- Published
- 1998
19. TGF- 2signaling in thymic epithelial cells regulates thymic involution and postirradiation reconstitution
- Author
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Hauri-Hohl, M, Zuklys, S, Keller, M, Jeker, LT, Barthlott, T, Moon, A, Roes, J, and Holländer, G
- Abstract
The thymus constitutes the primary lymphoid organ responsible for the generation of naive T cells. Its stromal compartment is largely composed of a scaffold of different subsets of epithelial cells that provide soluble and membrane-bound molecules essential for thymocyte maturation and selection. With senescence, a steady decline in the thymic output of T cells has been observed. Numeric and qualitative changes in the stromal compartment of the thymus resulting in re-duced thymopoietic capacity have been suggested to account for this physiologic process. The precise cellular and molecular mechanisms underlying thymic senescence are, however, only incompletely understood. Here, we demonstrate that TGF-β signaling in thymic epithelial cells exerts a direct influence on the cell's capacity to support thymopoiesis in the aged mouse as the physiologic process of thymic senescence is mitigated in mice deficient for the expression of TGF-ßRII on thymic epithelial cells. Moreover, TGF-ß signaling in these stromal cells transiently hinders the early phase of thymic reconstitution after myeloablative conditioning and hematopoietic stem cell transplantation. Hence, inhibition of TGF-ß signaling decelerates the process of age-related thymic involution and may hasten the reconstitution of regular thymopoiesis after hematopoietic stem cell transplantation. © 2008 by The American Society of Hematology.
- Published
- 2008
20. A short primer on early molecular and cellular events in thymus organogenesis and replacement
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Barthlott, T, primary, Keller, MP, additional, and Hollnder, GA, additional
- Published
- 2006
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21. CD25+CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production
- Author
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Barthlott, T., primary
- Published
- 2005
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22. Immature T cells in peripheral lymphoid organs of recombinase-activating gene-1/-2-deficient mice. Thymus dependence and responsiveness to anti-CD3 epsilon antibody.
- Author
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Falk, I, primary, Potocnik, A J, additional, Barthlott, T, additional, Levelt, C N, additional, and Eichmann, K, additional
- Published
- 1996
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23. A novel mouse thymocyte antigen (F3Ag): down-regulation during the CD4+CD8+ double-positive stage indicates positive selection.
- Author
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Barthlott, T, Potocnik, A J, Kohler, H, Carsetti, R, Pircher, H, Fowlkes, B J, and Eichmann, K
- Abstract
We describe a novel mAb (F3) which reacts with a 65 kDa thymocyte surface protein, expressed on approximately 80% of thymocytes, referred to as F3Ag. In ontogeny, F3Ag expression begins in the CD4(-)CD8(-) double-negative (DN) CD25(+) population and is maintained through approximately 85% of the CD4(+)CD8(+) double-positive (DP) stage. DP cells with high TCR expression and CD4(+) single-positive (SP) cells are predominantly negative for F3Ag, whereas many CD8(+) SP thymocytes express F3Ag. F3Ag-DP thymocytes show a reduced expression of RAG-1 and RAG-2 compared with F3Ag+ DP cells. The shutdown of F3Ag expression during the DP stage is related to positive selection: mice deficient for MHC class I and class II molecules maintain F3Ag expression in almost all DP cells. Transgenic (tg) mice carrying TCR restricted for MHC class II show a more pronounced down-regulation of F3Ag in the DP compartment than normal mice, depending on the presence of a positively selecting MHC. The size of the F3Ag- DP subset is positively correlated with the efficacy of positive selection into the CD4(+) SP compartment. Because some CD8(+) SP cells express F3Ag, the relationship between F3Ag down-regulation and positive selection is less obvious in DP cells of mice carrying MHC class I-restricted tg TCR. However, in reaggregate thymic organ cultures, sorted F3Ag- DP cells differentiate into CD8(+) SP cells more rapidly than do F3Ag+ DP cells. Thus, after down-regulation in the DP stage, a proportion of CD8(+) SP cells appears to re-express F3Ag. In addition, the proportion of F3Ag-CD8(+) SP cells depends on the efficacy of positive selection into the CD8 lineage. Taken together, the regulation of the expression of the F3Ag appears to be associated with signals that control thymic repertoire selection.
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- 1996
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24. Thymic epithelial organoids mediate T-cell development.
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Hübscher T, Lorenzo-Martín LF, Barthlott T, Tillard L, Langer JJ, Rouse P, Blackburn CC, Holländer G, and Lutolf MP
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- Animals, Mice, Cell Proliferation, Mice, Inbred C57BL, Stem Cells cytology, Stem Cells metabolism, Organoids cytology, Thymus Gland cytology, T-Lymphocytes cytology, T-Lymphocytes metabolism, T-Lymphocytes immunology, Epithelial Cells cytology, Epithelial Cells metabolism, Cell Differentiation
- Abstract
Although the advent of organoids has opened unprecedented perspectives for basic and translational research, immune system-related organoids remain largely underdeveloped. Here, we established organoids from the thymus, the lymphoid organ responsible for T-cell development. We identified conditions enabling mouse thymic epithelial progenitor cell proliferation and development into organoids with diverse cell populations and transcriptional profiles resembling in vivo thymic epithelial cells (TECs) more closely than traditional TEC cultures. In contrast to these two-dimensional cultures, thymic epithelial organoids maintained thymus functionality in vitro and mediated physiological T-cell development upon reaggregation with T-cell progenitors. The reaggregates showed in vivo-like epithelial diversity and the ability to attract T-cell progenitors. Thymic epithelial organoids are the first organoids originating from the stromal compartment of a lymphoid organ. They provide new opportunities to study TEC biology and T-cell development in vitro, paving the way for future thymic regeneration strategies in ageing or acute injuries., Competing Interests: Competing interests M.P.L. is an employee of F. Hoffmann-La Roche., (© 2024. Published by The Company of Biologists Ltd.)
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- 2024
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25. Indispensable epigenetic control of thymic epithelial cell development and function by polycomb repressive complex 2.
- Author
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Barthlott T, Handel AE, Teh HY, Wirasinha RC, Hafen K, Žuklys S, Roch B, Orkin SH, de Villartay JP, Daley SR, and Holländer GA
- Subjects
- Animals, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes metabolism, Cell Differentiation, Cell Lineage, Epithelial Cells physiology, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Polycomb Repressive Complex 2 metabolism, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes cytology, T-Lymphocytes physiology, Thymocytes cytology, Thymocytes physiology, Thymus Gland physiology, Mice, Epigenesis, Genetic, Epithelial Cells cytology, Polycomb Repressive Complex 2 genetics, Thymus Gland cytology
- Abstract
Thymic T cell development and T cell receptor repertoire selection are dependent on essential molecular cues provided by thymic epithelial cells (TEC). TEC development and function are regulated by their epigenetic landscape, in which the repressive H3K27me3 epigenetic marks are catalyzed by polycomb repressive complex 2 (PRC2). Here we show that a TEC-targeted deficiency of PRC2 function results in a hypoplastic thymus with reduced ability to express antigens and select a normal repertoire of T cells. The absence of PRC2 activity reveals a transcriptomically distinct medullary TEC lineage that incompletely off-sets the shortage of canonically-derived medullary TEC whereas cortical TEC numbers remain unchanged. This alternative TEC development is associated with the generation of reduced TCR diversity. Hence, normal PRC2 activity and placement of H3K27me3 marks are required for TEC lineage differentiation and function and, in their absence, the thymus is unable to compensate for the loss of a normal TEC scaffold.
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- 2021
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26. Thymus Extracellular Matrix-Derived Scaffolds Support Graft-Resident Thymopoiesis and Long-Term In Vitro Culture of Adult Thymic Epithelial Cells.
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Asnaghi MA, Barthlott T, Gullotta F, Strusi V, Amovilli A, Hafen K, Srivastava G, Oertle P, Toni R, Wendt D, Holländer GA, and Martin I
- Abstract
The thymus provides the physiological microenvironment critical for the development of T lymphocytes, the cells that orchestrate the adaptive immune system to generate an antigen-specific response. A diverse population of stroma cells provides surface-bound and soluble molecules that orchestrate the intrathymic maturation and selection of developing T cells. Forming an intricate 3D architecture, thymic epithelial cells (TEC) represent the most abundant and important constituent of the thymic stroma. Effective models for in and ex vivo use of adult TEC are still wanting, limiting the engineering of functional thymic organoids and the understanding of the development of a competent immune system. Here a 3D scaffold is developed based on decellularized thymic tissue capable of supporting in vitro and in vivo thymopoiesis by both fetal and adult TEC. For the first time, direct evidences of feasibility for sustained graft-resident T-cell development using adult TEC as input are provided. Moreover, the scaffold supports prolonged in vitro culture of adult TEC, with a retained expression of the master regulator Foxn1. The success of engineering a thymic scaffold that sustains adult TEC function provides unprecedented opportunities to investigate thymus development and physiology and to design and implement novel strategies for thymus replacement therapies., Competing Interests: Philipp Oertle is a shareholder in ARTIDIS AG. Gitika Srivastava and Philipp Oertle are employed by ARTIDIS AG. The other authors declare no conflict of interest., (© 2021 The Authors. Advanced Functional Materials published by Wiley‐VCH GmbH.)
- Published
- 2021
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27. Differential Response of Mouse Thymic Epithelial Cell Types to Ionizing Radiation-Induced DNA Damage.
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Calvo-Asensio I, Barthlott T, von Muenchow L, Lowndes NF, and Ceredig R
- Abstract
Thymic epithelial cells (TECs) are the main components of the thymic stroma that support and control T-cell development. Preparative regimens using DNA-damaging agents, such as total body irradiation and/or chemotherapeutic drugs, that are necessary prior to bone marrow transplantation (BMT) have profound deleterious effects on the hematopoietic system, including the thymic stroma, which may be one of the main causes for the prolonged periods of T-cell deficiency and the inefficient T cell reconstitution that are common following BMT. The DNA damage response (DDR) is a complex signaling network that allows cells to respond to all sorts of genotoxic insults. Hypoxia is known to modulate the DDR and play a role affecting the survival capacity of different cell types. In this study, we have characterized in detail the DDR of cortical and medullary TEC lines and their response to ionizing radiation, as well as the effects of hypoxia on their DDR. Although both mTECs and cTECs display relatively high radio-resistance, mTEC cells have an increased survival capacity to ionizing radiation (IR)-induced DNA damage, and hypoxia specifically decreases the radio-resistance of mTECs by upregulating the expression of the pro-apoptotic factor Bim. Analysis of the expression of TEC functional factors by primary mouse TECs showed a marked decrease of highly important genes for TEC function and confirmed cTECs as the most affected cell type by IR. These findings have important implications for improving the outcomes of BMT and promoting successful T cell reconstitution.
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- 2017
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28. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells.
- Author
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Žuklys S, Handel A, Zhanybekova S, Govani F, Keller M, Maio S, Mayer CE, Teh HY, Hafen K, Gallone G, Barthlott T, Ponting CP, and Holländer GA
- Subjects
- Animals, Antigen Presentation genetics, Cell Communication, Cell Differentiation genetics, Cell Lineage genetics, Cells, Cultured, Clonal Selection, Antigen-Mediated genetics, Forkhead Transcription Factors genetics, Gene Expression Regulation, Genome genetics, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Epithelial Cells physiology, Forkhead Transcription Factors metabolism, Precursor Cells, T-Lymphoid physiology, T-Lymphocytes physiology, Thymus Gland physiology
- Abstract
Thymic epithelial cell differentiation, growth and function depend on the expression of the transcription factor Foxn1; however, its target genes have never been physically identified. Using static and inducible genetic model systems and chromatin studies, we developed a genome-wide map of direct Foxn1 target genes for postnatal thymic epithelia and defined the Foxn1 binding motif. We determined the function of Foxn1 in these cells and found that, in addition to the transcriptional control of genes involved in the attraction and lineage commitment of T cell precursors, Foxn1 regulates the expression of genes involved in antigen processing and thymocyte selection. Thus, critical events in thymic lympho-stromal cross-talk and T cell selection are indispensably choreographed by Foxn1., Competing Interests: The authors declare no competing financial interests.
- Published
- 2016
- Full Text
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29. Cell Growth Dynamics in Embryonic and Adult Mouse Thyroid Revealed by a Novel Approach to Detect Thyroid Gland Subpopulations.
- Author
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Gawade S, Mayer C, Hafen K, Barthlott T, Krenger W, and Szinnai G
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- Animals, Antibodies chemistry, Cell Differentiation, Cell Proliferation, Cell Separation, Epithelial Cells cytology, Female, Fibroblasts cytology, Flow Cytometry, Mesoderm cytology, Mice, Thyroid Gland cytology, Thyroid Gland embryology
- Abstract
Background: The thyroid is composed of endocrine epithelial cells, blood vessels, and mesenchyme. However, no data exist thus far on absolute cell numbers, relative distribution, and proliferation of the different cell populations in the developing and mature thyroid. The aim of this study was therefore to establish a flow cytometry protocol that allows detection and quantification of discrete cell populations in embryonic and adult murine thyroid tissues., Methods: Cell-type anti-mouse specific antibodies were used for erythroid cells (Ter119), hematopoietic cells (CD45), epithelial cells (EpCam/CD326, E-cadherin/CD324), thyroid follicular cells and C-cells (Nkx2-1), endothelial cells (Pecam/CD31, Icam-1/CD54), and fibroblasts (PDGFRa/CD140a). Proliferating cells were detected after labeling with 5-bromo-2'-deoxyuridine (BrdU). For flow cytometry analyses, micro-dissected embryonic (E) and adult thyroids were pooled (E13.5, n = 25; E15.5, n = 15; E17.5, n = 15; adult, n = 4) in one sample., Results: The absolute parenchymal cell numbers per mouse thyroid (M ± SD), excluding the large number of CD45(+) and Ter119(+) cells, increased from 7425 ± 1338 at E13.5 to 271,561 ± 22,325 in adult tissues. As expected, Nkx2-1(+) cells represented the largest cell population in adult tissues (61.2 ± 1.1%). Surprisingly, at all three embryonic stages analyzed, thyroid follicular cells and C-cells accounted only for a small percentage of the total thyroid cell mass (between 4.7 ± 0.4% and 9.4 ± 1.6%). In contrast, the largest cell population at all three embryonic stages was identified as PDGFRa/CD140a(+) fibroblasts (61.4 ± 0.4% to 77.3 ± 1.1%). However, these cells represented the smallest population in adult tissues (5.2 ± 0.8%). Pecam/CD31(+) endothelial cells increased from E13.5 to E15.5 from 3.7 ± 0.8% to 8.5 ± 3.0%, then remained stable at E17.5 and adult tissues. Proliferation rates were sizable during the entire organogenesis but differed between cell populations, with distinct proliferative peaks at E13.5 in epithelial cells (32.7 ± 0.6% BrdU(+) cells), and at E15.5 in endothelial cells (22.4 ± 2.4% BrdU(+) cells). Fibroblasts showed a constant proliferation rate in embryonic tissues. In adult tissues, BrdU(+) cells were between 0.1% and 0.4% in all cell types., Conclusions: Using a novel flow cytometry-based method, a previously unobserved highly dynamic growth pattern of thyroid cell populations during embryogenesis was uncovered. This approach will provide a useful new tool for cell function analyses in murine thyroid disease models.
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- 2016
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30. The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility.
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Tang F, Gill J, Ficht X, Barthlott T, Cornils H, Schmitz-Rohmer D, Hynx D, Zhou D, Zhang L, Xue G, Grzmil M, Yang Z, Hergovich A, Hollaender GA, Stein JV, Hemmings BA, and Matthias P
- Subjects
- Actins physiology, Animals, Apoptosis, Cell Movement, Chemotaxis, Cytoskeleton ultrastructure, Lymphocyte Count, Lymphoid Tissue pathology, Lymphopenia pathology, Mice, Mice, Knockout, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, T-Lymphocyte Subsets cytology, rho GTP-Binding Proteins physiology, Lymphocytes cytology, Lymphopenia enzymology, Protein Serine-Threonine Kinases physiology, Thymocytes cytology, Thymus Gland pathology, Transendothelial and Transepithelial Migration physiology
- Abstract
The serine and threonine kinase MST1 is the mammalian homolog of Hippo. MST1 is a critical mediator of the migration, adhesion, and survival of T cells; however, these functions of MST1 are independent of signaling by its typical effectors, the kinase LATS and the transcriptional coactivator YAP. The kinase NDR1, a member of the same family of kinases as LATS, functions as a tumor suppressor by preventing T cell lymphomagenesis, which suggests that it may play a role in T cell homeostasis. We generated and characterized mice with a T cell-specific double knockout of Ndr1 and Ndr2 (Ndr DKO). Compared with control mice, Ndr DKO mice exhibited a substantial reduction in the number of naïve T cells in their secondary lymphoid organs. Mature single-positive thymocytes accumulated in the thymus in Ndr DKO mice. We also found that NDRs acted downstream of MST1 to mediate the egress of mature thymocytes from the thymus, as well as the interstitial migration of naïve T cells within popliteal lymph nodes. Together, our findings indicate that the kinases NDR1 and NDR2 function as downstream effectors of MST1 to mediate thymocyte egress and T cell migration., (Copyright © 2015, American Association for the Advancement of Science.)
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- 2015
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31. A subpopulation of CD103(pos) ICOS(pos) Treg cells occurs at high frequency in lymphopenic mice and represents a lymph node specific differentiation stage.
- Author
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Barthlott T, Bosch AJ, Berkemeier C, Nogales-Cadenas R, Jeker LT, Keller MP, Pascual-Montano A, and Holländer GA
- Subjects
- Animals, Cell Differentiation immunology, Cellular Microenvironment, Cluster Analysis, Cytokines metabolism, Gene Expression Profiling, Homeostasis, Interleukin-7 metabolism, Lymphocyte Count, Lymphopenia metabolism, Mice, Signal Transduction, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, T-Lymphocytes, Regulatory cytology, Thymic Stromal Lymphopoietin, Antigens, CD metabolism, Inducible T-Cell Co-Stimulator Protein metabolism, Integrin alpha Chains metabolism, Lymph Nodes immunology, Lymphopenia blood, Lymphopenia immunology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism
- Abstract
Regulatory T (Treg) cells are pivotal for the maintenance of peripheral tolerance by controlling self-reactive, chronic, and homeostatic T-cell responses. Here, we report that the increase in Treg-cell suppressive function observed in lymphopenic mice correlates with the degree of lymphopenia and is caused by a higher frequency of a novel subpopulation of CD103(pos) ICOS(pos) Treg cells. Though present in the thymus, CD103(pos) ICOS(pos) Treg cells are not generated there but recirculate from the periphery to that site. The acquisition and maintenance of this distinctive phenotype requires the LN microenvironment and the in situ availability of antigen. Contrary to conventional effector and other Treg cells, the cellularity of CD103(pos) ICOS(pos) Treg cells is not affected by the absence of IL-7 and thymic stroma lymphopoetin. Given their increased frequency in lymphopenia, the absolute number of CD103(pos) ICOS(pos) Treg cells remains unchanged in the periphery irrespective of a paucity of total Treg cells. We furthermore demonstrate, with cell transfers in mice, that the CD103(pos) ICOS(pos) phenotype represents a LN-specific differentiation stage arrived at by several other Treg-cell subsets. Thus, tissue-specific cues determine the overall potency of the peripheral Treg-cell pool by shaping its subset composition., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2015
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32. Violation of the 12/23 rule of genomic V(D)J recombination is common in lymphocytes.
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Parkinson NJ, Roddis M, Ferneyhough B, Zhang G, Marsden AJ, Maslau S, Sanchez-Pearson Y, Barthlott T, Humphreys IR, Ladell K, Price DA, Ponting CP, Hollander G, and Fischer MD
- Subjects
- Animals, Cell Differentiation genetics, Gene Rearrangement, Genes, RAG-1, Humans, Lymphocytes cytology, Mice, Mice, Knockout, Models, Biological, Sequence Analysis, DNA, Genomics, Lymphocytes metabolism, V(D)J Recombination
- Abstract
V(D)J genomic recombination joins single gene segments to encode an extensive repertoire of antigen receptor specificities in T and B lymphocytes. This process initiates with double-stranded breaks adjacent to conserved recombination signal sequences that contain either 12- or 23-nucleotide spacer regions. Only recombination between signal sequences with unequal spacers results in productive coding genes, a phenomenon known as the "12/23 rule." Here we present two novel genomic tools that allow the capture and analysis of immune locus rearrangements from whole thymic and splenic tissues using second-generation sequencing. Further, we provide strong evidence that the 12/23 rule of genomic recombination is frequently violated under physiological conditions, resulting in unanticipated hybrid recombinations in ∼10% of Tcra excision circles. Hence, we demonstrate that strict adherence to the 12/23 rule is intrinsic neither to recombination signal sequences nor to the catalytic process of recombination and propose that nonclassical excision circles are liberated during the formation of antigen receptor diversity., (© 2015 Parkinson et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2015
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33. MicroRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection.
- Author
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Zuklys S, Mayer CE, Zhanybekova S, Stefanski HE, Nusspaumer G, Gill J, Barthlott T, Chappaz S, Nitta T, Dooley J, Nogales-Cadenas R, Takahama Y, Finke D, Liston A, Blazar BR, Pascual-Montano A, and Holländer GA
- Subjects
- Animals, Cell Differentiation genetics, Cell Lineage genetics, DEAD-box RNA Helicases deficiency, Epithelial Cells pathology, Mice, Mice, Nude, Mice, Transgenic, MicroRNAs antagonists & inhibitors, Mutation, Organ Culture Techniques, Ribonuclease III deficiency, Stromal Cells immunology, Stromal Cells metabolism, Stromal Cells pathology, T-Lymphocytes cytology, T-Lymphocytes metabolism, Thymus Gland embryology, Cell Differentiation immunology, Cell Lineage immunology, Epithelial Cells immunology, Epithelial Cells metabolism, MicroRNAs physiology, T-Lymphocytes immunology, Thymus Gland immunology, Thymus Gland metabolism
- Abstract
Thymic epithelial cells provide unique cues for the lifelong selection and differentiation of a repertoire of functionally diverse T cells. Rendered microRNA (miRNA) deficient, these stromal cells in the mouse lose their capacity to instruct the commitment of hematopoietic precursors to a T cell fate, to effect thymocyte positive selection, and to achieve promiscuous gene expression required for central tolerance induction. Over time, the microenvironment created by miRNA-deficient thymic epithelia assumes the cellular composition and structure of peripheral lymphoid tissue, where thympoiesis fails to be supported. These findings emphasize a global role for miRNA in the maintenance and function of the thymic epithelial cell scaffold and establish a novel mechanism how these cells control peripheral tissue Ag expression to prompt central immunological tolerance.
- Published
- 2012
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34. Maintenance of a normal thymic microenvironment and T-cell homeostasis require Smad4-mediated signaling in thymic epithelial cells.
- Author
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Jeker LT, Barthlott T, Keller MP, Zuklys S, Hauri-Hohl M, Deng CX, and Holländer GA
- Subjects
- Animals, Base Sequence, Chemokines genetics, DNA, Complementary genetics, Epithelial Cells cytology, Epithelial Cells metabolism, Female, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells immunology, Hematopoietic Stem Cells metabolism, Homeostasis, Male, Mice, Mice, Mutant Strains, Mice, Transgenic, Pregnancy, Signal Transduction, Smad4 Protein deficiency, Smad4 Protein genetics, T-Lymphocytes immunology, Thymus Gland immunology, Transcription, Genetic, Smad4 Protein metabolism, T-Lymphocytes cytology, T-Lymphocytes metabolism, Thymus Gland cytology, Thymus Gland metabolism
- Abstract
Signals mediated by the transforming growth factor-beta superfamily of growth factors have been implicated in thymic epithelial cell (TEC) differentiation, homeostasis, and function, but a direct reliance on these signals has not been established. Here we demonstrate that a block in canonical transforming growth factor-beta signaling by the loss of Smad4 expression in TECs leads to qualitative changes in TEC function and a progressively disorganized thymic microenvironment. Moreover, the number of thymus resident early T-lineage progenitors is severely reduced in the absence of Smad4 expression in TECs and directly correlates with extensive thymic and peripheral lymphopenia. Our observations hence place Smad4 within the signaling events in TECs that determine total thymus cellularity by controlling the number of early T-lineage progenitors.
- Published
- 2008
- Full Text
- View/download PDF
35. TGF-beta signaling in thymic epithelial cells regulates thymic involution and postirradiation reconstitution.
- Author
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Hauri-Hohl MM, Zuklys S, Keller MP, Jeker LT, Barthlott T, Moon AM, Roes J, and Holländer GA
- Subjects
- Animals, Mice, Signal Transduction, Stromal Cells, Thymus Gland cytology, Aging physiology, Epithelial Cells physiology, Hematopoietic Stem Cell Transplantation adverse effects, Regeneration, Thymus Gland physiology, Transforming Growth Factor beta physiology
- Abstract
The thymus constitutes the primary lymphoid organ responsible for the generation of naive T cells. Its stromal compartment is largely composed of a scaffold of different subsets of epithelial cells that provide soluble and membrane-bound molecules essential for thymocyte maturation and selection. With senescence, a steady decline in the thymic output of T cells has been observed. Numeric and qualitative changes in the stromal compartment of the thymus resulting in reduced thymopoietic capacity have been suggested to account for this physiologic process. The precise cellular and molecular mechanisms underlying thymic senescence are, however, only incompletely understood. Here, we demonstrate that TGF-beta signaling in thymic epithelial cells exerts a direct influence on the cell's capacity to support thymopoiesis in the aged mouse as the physiologic process of thymic senescence is mitigated in mice deficient for the expression of TGF-beta RII on thymic epithelial cells. Moreover, TGF-beta signaling in these stromal cells transiently hinders the early phase of thymic reconstitution after myeloablative conditioning and hematopoietic stem cell transplantation. Hence, inhibition of TGF-beta signaling decelerates the process of age-related thymic involution and may hasten the reconstitution of regular thymopoiesis after hematopoietic stem cell transplantation.
- Published
- 2008
- Full Text
- View/download PDF
36. EVA regulates thymic stromal organisation and early thymocyte development.
- Author
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DeMonte L, Porcellini S, Tafi E, Sheridan J, Gordon J, Depreter M, Blair N, Panigada M, Sanvito F, Merati B, Albientz A, Barthlott T, Ozmen L, Blackburn CC, and Guttinger M
- Subjects
- Animals, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, T-Lymphocyte Subsets physiology, Thymus Gland cytology, Thymus Gland metabolism, Cell Adhesion Molecules physiology, Gene Expression Regulation, Developmental physiology, Thymus Gland growth & development
- Abstract
Epithelial V-like antigen (EVA) is an immunoglobulin-like adhesion molecule identified in a screen for molecules developmentally regulated at the DN to DP progression in thymocyte development. We show that EVA is expressed during the early stages of thymus organogenesis in both fetal thymic epithelia and T cell precursors, and is progressively downregulated from day 16.5 of embryonic development. In the postnatal thymus, EVA expression is restricted to epithelial cells and is distributed throughout both cortical and medullary thymic regions. Transgenic overexpression of EVA in the thymus cortex resulted in a modified stromal environment, which elicited an increase in organ size and absolute cell number. Although peripheral T lymphocyte numbers are augmented throughout life, no imbalance either in the repertoire, or in the different T cell subsets was detected. Collectively, these data suggest a role for EVA in structural organisation of the thymus and early lymphocyte development.
- Published
- 2007
- Full Text
- View/download PDF
37. A short primer on early molecular and cellular events in thymus organogenesis and replacement.
- Author
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Barthlott T, Keller MP, Krenger W, and Holländer GA
- Abstract
Haematopoietic precursors have to undergo a complex series of maturational steps in the thymus before they exit into the periphery as functional T lymphocytes. Thymic stroma cells, the majority being of epithelial origin, provide the functional partners for the maturational progression along this differentiation pathway. Here we review some of the molecular and cellular mechanisms that account for thymus organogenesis and discuss a strategy to use thymic epithelial precursor cells for the regeneration of the thymic microenvironment.
- Published
- 2007
38. CD25+ CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production.
- Author
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Barthlott T, Moncrieffe H, Veldhoen M, Atkins CJ, Christensen J, O'Garra A, and Stockinger B
- Subjects
- Animals, Cell Line, Down-Regulation, Interleukin-2 genetics, Mice, RNA, Messenger metabolism, Receptors, Interleukin-2 analysis, CD4-Positive T-Lymphocytes immunology, Interleukin-10 biosynthesis, Interleukin-2 metabolism, Receptors, Interleukin-2 metabolism, T-Lymphocyte Subsets immunology
- Abstract
Maintenance of homeostasis in the immune system involves competition for resources between T lymphocytes, which avoids the development of immune pathology seen in lymphopenic mice. CD25+ CD4+ T cells are important for homeostasis, but there is as yet no consensus on their mechanisms of action. Although CD25+ CD4+ T cells cause substantial down-regulation of IL-2 mRNA in responder T cells in an in vitro co-culture system, the presence of IL-protein can be demonstrated by intracellular staining. As a consequence of competition for IL-2, CD25+ CD4+ T cells further up-regulate the IL-2R alpha chain (CD25), a process that is strictly dependent on IL-2, whereas responder T cells fail to up-regulate CD25. Similarly, adoptive transfer into lymphopenic mice showed that CD25+ CD4+ T cells interfere with CD25 up-regulation on co-transferred naive T cells, while increasing their own CD25 levels. IL-2 sequestration by CD25+ CD4+ T cells is not a passive phenomenon but instead initiates--in conjunction with signals through the TCR--their differentiation to IL-10 production. Although IL-10 is not required for in vitro suppression, it is vital for the in vivo function of regulatory T cells. Our data provide a link explaining the apparent difference in regulatory mechanisms in vitro and in vivo.
- Published
- 2005
- Full Text
- View/download PDF
39. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells.
- Author
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Vieira PL, Christensen JR, Minaee S, O'Neill EJ, Barrat FJ, Boonstra A, Barthlott T, Stockinger B, Wraith DC, and O'Garra A
- Subjects
- Administration, Intranasal, Animals, Antigens administration & dosage, CD4-Positive T-Lymphocytes metabolism, Cell Division immunology, Cells, Cultured, Interleukin-10 physiology, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Myelin Basic Protein administration & dosage, Myelin Basic Protein immunology, Peptide Fragments administration & dosage, Peptide Fragments immunology, CD4-Positive T-Lymphocytes immunology, Interleukin-10 metabolism, Receptors, Interleukin-2 biosynthesis, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism
- Abstract
Regulatory T cells (T(Reg)) control immune responses to self and nonself Ags. The relationship between Ag-driven IL-10-secreting T(Reg) (IL-10-T(Reg)) and naturally occurring CD4(+)CD25(+) T(Reg) is as yet unclear. We show that mouse IL-10-T(Reg) obtained using either in vitro or in vivo regimens of antigenic stimulation did not express the CD4(+)CD25(+) T(Reg)-associated transcription factor Foxp3. However, despite the absence of Foxp3 expression, homogeneous populations of IL-10-T(Reg) inhibited the in vitro proliferation of CD4(+)CD25(-) T cells with a similar efficiency to that of CD4(+)CD25(+) T(Reg). This inhibition of T cell proliferation by IL-10-T(Reg) was achieved through an IL-10-independent mechanism as seen for CD4(+)CD25(+) T(Reg) and was overcome by exogenous IL-2. Both IL-10-T(Reg) and CD4(+)CD25(+) T(Reg) were similar in that they produced little to no IL-2. These data show that Foxp3 expression is not a prerequisite for IL-10-T(Reg) activity in vitro or in vivo, and suggest that IL-10-T(Reg) and naturally occurring CD4(+)CD25(+) T(Reg) may have distinct origins.
- Published
- 2004
- Full Text
- View/download PDF
40. Factors affecting the susceptibility of the mouse pituitary gland to CD8 T-cell-mediated autoimmunity.
- Author
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De Jersey J, Carmignac D, Le Tissier P, Barthlott T, Robinson I, and Stockinger B
- Subjects
- Animals, CD8 Antigens immunology, Epitopes immunology, Growth Hormone deficiency, Growth Hormone immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nucleocapsid Proteins, Nucleoproteins analysis, Orthomyxoviridae Infections immunology, Phenotype, Pituitary Diseases immunology, Radioimmunoassay methods, Receptors, Antigen, T-Cell immunology, Reverse Transcriptase Polymerase Chain Reaction methods, Viral Core Proteins analysis, Autoimmunity immunology, CD8-Positive T-Lymphocytes immunology, Pituitary Gland, Anterior immunology, RNA-Binding Proteins
- Abstract
We have previously shown, in a transgenic mouse model, that the pituitary gland is susceptible to CD8 T-cell-mediated autoimmunity, triggered by a cell-specific model autoantigen, resulting in pan-anterior pituitary hypophysitis and dwarfism. In the present study, we now demonstrate that antigen dose, the T-cell precursor frequency, the degree of lymphopenia and the context of target antigen expression, are important parameters determining the time course and extent of the pathological consequences of CD8 T-cell-mediated autoimmunity. Furthermore, our data indicate that the pituitary gland is susceptible to CD8 autoimmunity following an inflammatory insult such as a viral infection. As lymphocytic hypophysitis may be manifest in other autoimmune conditions, and the pituitary gland may be susceptible to T-cell-mediated pathology after immunization with a virus expressing soluble pituitary antigen, it is important to consider that strategies based on vaccination against soluble pituitary gonadotrophins could have other unexpected endocrine consequences.
- Published
- 2004
- Full Text
- View/download PDF
41. T cell regulation as a side effect of homeostasis and competition.
- Author
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Barthlott T, Kassiotis G, and Stockinger B
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, H-2 Antigens immunology, Homeodomain Proteins physiology, Leukocyte Common Antigens analysis, Lymphopenia immunology, Mice, Mice, Inbred C57BL, Receptors, Interleukin-2 analysis, Antigens immunology, Homeostasis, T-Lymphocytes immunology
- Abstract
We have previously hypothesized that maintaining a balanced peripheral immune system may not be the sole responsibility of a specialized subset of T cells dedicated to immune regulation, but also a side effect of normal competition for shared resources within an intact immune system. Here we show that regulatory activity is correlated with high homeostatic expansion potential, reflecting the avidity for self-peptide:MHC complexes. Monoclonal transgenic T cells with high homeostatic expansion potential and lacking characteristics previously associated with regulatory function were able to regulate wasting disease induced by transfer of a small number of naive CD45RB(hi) CD4 T cells into lymphopenic hosts. Self-regulatory function is also found in the naive polyclonal T cell repertoire depleted of CD25(+) T cells. T cells capable of preventing immune pathology, like the transgenic T cells, express higher than average levels of CD5, an indicator of avidity for self:MHC peptide complexes. We therefore propose that dysregulated expansion of potentially pathogenic T cells in a lymphopenic environment can be prevented by members of the naive T cell repertoire, irrespective of their specificity, as a side effect of their response to homeostatic and antigenic stimulation.
- Published
- 2003
- Full Text
- View/download PDF
42. Activation of CD8 T cells by antigen expressed in the pituitary gland.
- Author
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de Jersey J, Carmignac D, Barthlott T, Robinson I, and Stockinger B
- Subjects
- Adoptive Transfer, Animals, Antigen Presentation genetics, Antigens, Viral biosynthesis, Autoantigens biosynthesis, Autoantigens physiology, CD8-Positive T-Lymphocytes virology, Cell Death immunology, Cell Movement genetics, Cell Movement immunology, Cytotoxicity, Immunologic, Dendritic Cells immunology, Dendritic Cells metabolism, Growth Hormone biosynthesis, Influenza A virus immunology, Interphase genetics, Interphase immunology, Lymph Nodes cytology, Lymph Nodes immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nucleocapsid Proteins, Nucleoproteins biosynthesis, Nucleoproteins genetics, Organ Specificity genetics, Organ Specificity immunology, Pituitary Gland, Anterior cytology, Pituitary Gland, Anterior virology, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets transplantation, Viral Core Proteins biosynthesis, Viral Core Proteins genetics, Antigens, Viral physiology, CD8-Positive T-Lymphocytes immunology, Lymphocyte Activation genetics, Nucleoproteins physiology, Pituitary Gland, Anterior immunology, Pituitary Gland, Anterior metabolism, RNA-Binding Proteins, Viral Core Proteins physiology
- Abstract
Ag expressed exclusively in the anterior pituitary gland and secreted locally by pituitary somatotrophs can gain access to the MHC class I presentation pathway and activate CD8 T cells. Influenza nucleoprotein (NP) was expressed as a transgene under the control of the human growth hormone (GH) locus control region. Activation of monoclonal F5 CD8 T cells specific for NP resulted in spontaneous autoimmune pathology of the pituitary gland in mice transgenic for both NP and the F5 TCR. Destruction of somatotrophs resulted in drastically reduced GH levels in adult mice and a dwarf phenotype. Adoptive transfer of F5 T cells into NP-transgenic hosts resulted in full T cell activation, first demonstrable in regional lymph nodes, followed by their migration to the pituitary gland. Despite the presence of activated, IFN-gamma-producing CD8 T cells in the pituitary gland and a slight reduction in pituitary GH levels, no effect on growth was observed. Thus, CD8 T cells have access to the neuroendocrine system and get fully activated in the absence of CD4 help, but Ag recognition in this location causes autoimmune pathology only in the presence of excessive CD8 T cell numbers.
- Published
- 2002
- Full Text
- View/download PDF
43. Lineage fate alteration of thymocytes developing in an MHC environment containing MHC/peptide ligands with antagonist properties.
- Author
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Barthlott T and Stockinger B
- Subjects
- Animals, CD4-Positive T-Lymphocytes, Ligands, Mice, Mice, Inbred C57BL, Receptors, Antigen, T-Cell physiology, Signal Transduction, Cell Lineage, H-2 Antigens physiology, Histocompatibility Antigens Class I physiology, T-Lymphocytes physiology
- Abstract
A18 TCR transgenic thymocytes which are H-2E(k) restricted and normally selected into the CD4 lineage, are exclusively selected into the CD8 lineage in an H-2(q) MHC background. CD8 T cell selection in the H-2(q) background is far more efficient than default selection of A18 CD8 cells on a CD4(-/-) H-2E(k +) background. This suggests the involvement of special selecting ligands. Analogues of the cognate peptide for A18 with antagonist properties for the A18 TCR have previously been shown to effect a lineage diversion from CD4 to CD8 in fetal thymic organ cultures and intriguingly the MHC(q) background contains unidentified natural MHC class II ligands which similarly show antagonist properties for the A18 TCR. Despite the presence of these unidentified MHC class II ligands in the H-2(q) background and their potential influence on developing A18 thymocytes, however, MHC class I molecules were essential for thymic selection of A18 CD8 T cells.
- Published
- 2001
- Full Text
- View/download PDF
44. T cell regulation: a special job or everyone's responsibility?
- Author
-
Stockinger B, Barthlott T, and Kassiotis G
- Subjects
- Animals, Autoimmune Diseases immunology, Lymphocyte Activation, Mice, Self Tolerance, T-Lymphocytes immunology
- Published
- 2001
- Full Text
- View/download PDF
45. Differential survival of naive CD4 and CD8 T cells.
- Author
-
Ferreira C, Barthlott T, Garcia S, Zamoyska R, and Stockinger B
- Subjects
- Animals, Apoptosis genetics, Apoptosis immunology, Biomarkers, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes metabolism, Cell Division genetics, Cell Division immunology, Cell Survival genetics, Cell Survival immunology, Cells, Cultured, Homeostasis genetics, Homeostasis immunology, Hyaluronan Receptors biosynthesis, Immunity, Innate, Interphase genetics, Interphase immunology, Leukocyte Common Antigens biosynthesis, Lymphocyte Activation genetics, Mice, Mice, Inbred A, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Thymectomy, Tumor Necrosis Factor Receptor Superfamily, Member 7 biosynthesis, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes immunology
- Abstract
In this paper we compare survival characteristics of transgenic and polyclonal CD4 and CD8 T cells. Transgenic CD4 T cells have an intrinsically lower capacity for survival, reflected in their gradual disappearance in thymectomized hosts, their increased sensitivity to apoptosis in vitro, and fewer divisions during homeostatic proliferation upon transfer into syngeneic lymphopenic hosts compared with CD8 T cells. Homeostatic proliferation, however, does not generally result in phenotypic conversion of activation markers unless cognate or cross-reactive Ag is present. T cells from the A18 TCR transgenic strain normally selected into the CD4 lineage are fragile as CD4 T cells, yet display the typical robust survival pattern of CD8 T cells when diverted into the CD8 lineage in a CD4-deficient host. Polyclonal CD4 and CD8 T cells also show distinctive patterns of survival, emphasizing that survival signals are relayed differently in the two lymphocyte subpopulations. However, expression levels of Bcl-2 in either transgenic or polyclonal naive CD4 and CD8 T cells are similar, excluding a role for this molecule as a key factor in differential survival of CD4 vs CD8 T cells.
- Published
- 2000
- Full Text
- View/download PDF
46. Antagonist peptide selects thymocytes expressing a class II major histocompatibility complex-restricted T cell receptor into the CD8 lineage.
- Author
-
Volkmann A, Barthlott T, Weiss S, Frank R, and Stockinger B
- Subjects
- Animals, Antigens, Differentiation, B-Lymphocyte genetics, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes immunology, Cell Differentiation drug effects, Cell Differentiation genetics, Cell Differentiation immunology, Crosses, Genetic, Lymphocyte Activation drug effects, Lymphocyte Activation genetics, Mice, Mice, Knockout, Mice, Transgenic, Organ Culture Techniques, Peptides pharmacology, T-Lymphocyte Subsets immunology, Thymus Gland cytology, Thymus Gland immunology, CD8-Positive T-Lymphocytes metabolism, Histocompatibility Antigens Class II genetics, Peptides immunology, Receptors, Antigen, T-Cell antagonists & inhibitors, Receptors, Antigen, T-Cell genetics, T-Lymphocyte Subsets metabolism
- Abstract
CD4/CD8 lineage decision is an important event during T cell maturation in the thymus. CD8 T cell differentiation usually requires corecognition of major histocompatibility complex (MHC) class I by the T cell receptor (TCR) and CD8, whereas CD4 T cells differentiate as a consequence of MHC class II recognition by the TCR and CD4. The involvement of specific peptides in the selection of T cells expressing a particular TCR could be demonstrated so far for the CD8 lineage only. We used mice transgenic for an MHC class II-restricted TCR to investigate the role of antagonistic peptides in CD4 T cell differentiation. Interestingly, antagonists blocked the development of CD4(+) cells that normally differentiate in thymus organ culture from those mice, and they induced the generation of CD8(+) cells in thymus organ culture from mice impaired in CD4(+) cell development (invariant chain-deficient mice). These results are in line with recent observations that antagonistic signals direct differentiation into the CD8 lineage, regardless of MHC specificity.
- Published
- 1998
- Full Text
- View/download PDF
47. Differentiation of CD4(high)CD8(low) coreceptor-skewed thymocytes into mature CD8 single-positive cells independent of MHC class I recognition.
- Author
-
Barthlott T, Kohler H, Pircher H, and Eichmann K
- Subjects
- Animals, Calcium metabolism, Cell Differentiation, Down-Regulation, Female, H-2 Antigens metabolism, In Vitro Techniques, Ion Transport, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Pregnancy, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, T-Lymphocyte Subsets metabolism, CD4 Antigens metabolism, CD8 Antigens metabolism, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets immunology
- Abstract
Thymocytes with a CD4(hi)CD8(lo) coreceptor-skewed (CRS) phenotype have been shown to contain precursors for CD8 single-positive (SP) thymocytes, in addition to precursors for CD4 SP cells. The selection mechanisms that stimulate CD4(hi)CD8(lo) cells to revert to the CD8 lineage are not known. Mice transgenic (tg) for the major histocompatibility complex (MHC) class I-restricted P14 T cell receptor (TCR), on the H-2bm13 background, generate a large number of CD4(hi)CD8(lo) CRS thymocytes. We analyzed the developmental potential and the differentiation requirements of the CD4(hi)CD8(lo) population of these mice. Using reaggregate thymic organ cultures (RTOC), we observed that these cells efficiently and almost exclusively differentiate into CD8 SP cells. Differentiation occurred independent of whether or not the MHC haplotype of the thymic stroma corresponds to the MHC restriction of the tg TCR. Loss of CD4 was independent of thymic stroma, up-regulation of CD8 to full levels was dependent on thymic stroma but independent of MHC haplotype. After trypsin treatment and overnight incubation, these CRS cells re-expressed CD8 but failed to re-express CD4, indicating that they are in the process of terminating CD4 synthesis. CD8 SP cells derived from the CRS cells proliferate in response to peptide-pulsed antigen-presenting cells. Our data suggest that CD4(hi)CD8(lo) CRS thymocytes bearing the P14 tg TCR have completed positive selection and differentiate autonomously into functionally competent CD8 SP cells.
- Published
- 1997
- Full Text
- View/download PDF
48. Asynchronous coreceptor downregulation after positive thymic selection: prolonged maintenance of the double positive state in CD8 lineage differentiation due to sustained biosynthesis of the CD4 coreceptor.
- Author
-
Barthlott T, Kohler H, and Eichmann K
- Subjects
- Animals, CD4 Antigens genetics, CD8-Positive T-Lymphocytes cytology, Cell Lineage, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Organ Culture Techniques, Protein Biosynthesis, Thymus Gland cytology, Transcription, Genetic, CD4 Antigens biosynthesis, CD8-Positive T-Lymphocytes immunology, Cell Differentiation immunology, Down-Regulation, Receptors, Antigen, T-Cell immunology, Thymus Gland immunology
- Abstract
In several experimental systems analyzing the generation of single positive (SP) thymocytes from double positive (DP) thymocytes, CD4 SP cells have been shown to appear before CD8 SP cells. This apparent temporal asymmetry in the maturation of CD4 SP and CD8 SP thymocytes could either be due to divergent molecular differentiation programs of the two T cell lineages, or merely to slower degradation kinetics of the CD4 protein. To study this question in unmanipulated in vivo differentiation, we developed a four-color flow cytometry protocol which identifies a recently activated TCRintCD69pos thymocyte population containing DP cells and early CD4 SP cells but no CD8 SP cells. We show that these TCRintCD69pos thymocytes represent a transitory stage in the mainstream alphabeta T cell lineage. The precursors of the CD8 SP cells are contained in this population as incompletely selected DP cells. Moreover, we show that expression of both coreceptors in the TCRintCD69pos population depends on transcriptional and translational activity, thus excluding differences in turnover rates of the CD4 and CD8 proteins as the cause of the asynchrony in differentiation of the CD4 and CD8 lineages.
- Published
- 1997
- Full Text
- View/download PDF
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