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Article: SAP modulates B cell functions in a genetic background-dependent manner

Detre, Cynthia / Yigit, Burcu / Keszei, Marton / Castro, Wilson / Magelky, Erica M / Terhorst, Cox

Immunology Letters. 2013 June, v. 153, no. 1-2

2013

Abstract: Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and ... ...

Abstract	Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP−/− CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP−/− animals. It is however not well understood whether in XLP patients and SAP−/− mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP−/− mice and in Rag−/− mice into which B cells derived from SAP−/− mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP−/− mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP−/− mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP−/− mice, suggests potentially novel therapeutic interventions in subsets of XLP patients.
Keywords	lymphoma ; antigens ; immunosuppression ; genetic background ; mutation ; mice ; homeostasis ; patients ; CD4-positive T-lymphocytes
Language	English
Dates of publication	2013-06
Size	p. 15-21.
Publishing place	Elsevier B.V.
Document type	Article
Note	2019-12-06
ZDB-ID	445150-8
ISSN	1879-0542 ; 0165-2478
ISSN (online)	1879-0542
ISSN	0165-2478
DOI	10.1016/j.imlet.2013.06.003
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Reproducibility of 2D GluCEST in healthy human volunteers at 7 T.

Nanga, Ravi Prakash Reddy / DeBrosse, Catherine / Kumar, Dushyant / Roalf, David / McGeehan, Brendan / D'Aquilla, Kevin / Borthakur, Arijitt / Hariharan, Hari / Reddy, Damodara / Elliott, Mark / Detre, John A / Epperson, Cynthia Neill / Reddy, Ravinder

Magnetic resonance in medicine

2018 Volume 80, Issue 5, Page(s) 2033–2039

Abstract: Purpose: To investigate the reproducibility of gray and white matter glutamate contrast of a brain slice among a small group of healthy volunteers by using the 2D single-slice glutamate CEST (GluCEST) imaging technique.: Methods: Six healthy ... ...

Abstract	Purpose: To investigate the reproducibility of gray and white matter glutamate contrast of a brain slice among a small group of healthy volunteers by using the 2D single-slice glutamate CEST (GluCEST) imaging technique. Methods: Six healthy volunteers were scanned multiple times for within-day and between-day reproducibility. One more volunteer was scanned for within-day reproducibility at 7T MRI. Glutamate CEST contrast measurements were calculated for within subjects and among the subjects and the coefficient of variations are reported. Results: The GluCEST measurements were highly reproducible in the gray and white matter area of the brain slice, whether it was within-day or between-day with a coefficient of variation of less than 5%. Conclusion: This preliminary study in a small group of healthy volunteers shows a high degree of reproducibility of GluCEST MRI in brain and holds promise for implementation in studying age-dependent changes in the brain.
MeSH term(s)	Adult ; Aged ; Brain/diagnostic imaging ; Brain/metabolism ; Female ; Glutamic Acid/chemistry ; Glutamic Acid/metabolism ; Humans ; Image Processing, Computer-Assisted/methods ; Magnetic Resonance Imaging/methods ; Magnetic Resonance Imaging/standards ; Male ; Middle Aged ; Reproducibility of Results
Chemical Substances	Glutamic Acid (3KX376GY7L)
Language	English
Publishing date	2018-05-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	605774-3
ISSN	1522-2594 ; 0740-3194
ISSN (online)	1522-2594
ISSN	0740-3194
DOI	10.1002/mrm.27362
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Article ; Online: SAP modulates B cell functions in a genetic background-dependent manner.

Detre, Cynthia / Yigit, Burcu / Keszei, Marton / Castro, Wilson / Magelky, Erica M / Terhorst, Cox

Immunology letters

2013 Volume 153, Issue 1-2, Page(s) 15–21

Abstract	Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP-/- CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP-/- animals. It is however not well understood whether in XLP patients and SAP-/- mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP-/- mice and in Rag-/- mice into which B cells derived from SAP-/- mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP-/- mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP-/- mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP-/- mice, suggests potentially novel therapeutic interventions in subsets of XLP patients.
MeSH term(s)	Animals ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/transplantation ; CD40 Antigens/immunology ; CD40 Antigens/metabolism ; Homeodomain Proteins/genetics ; Intracellular Signaling Peptides and Proteins/genetics ; Leukosialin/metabolism ; Lymphocyte Activation/immunology ; Lymphoproliferative Disorders/genetics ; Lymphoproliferative Disorders/immunology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Signaling Lymphocytic Activation Molecule Associated Protein
Chemical Substances	CD40 Antigens ; Homeodomain Proteins ; Intracellular Signaling Peptides and Proteins ; Leukosialin ; Sh2d1a protein, mouse ; Signaling Lymphocytic Activation Molecule Associated Protein ; RAG-1 protein (128559-51-3)
Language	English
Publishing date	2013-06-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	445150-8
ISSN	1879-0542 ; 0165-2478
ISSN (online)	1879-0542
ISSN	0165-2478
DOI	10.1016/j.imlet.2013.06.003
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Article ; Online: Receptor signaling lymphocyte-activation molecule family 1 (Slamf1) regulates membrane fusion and NADPH oxidase 2 (NOX2) activity by recruiting a Beclin-1/Vps34/ultraviolet radiation resistance-associated gene (UVRAG) complex.

Ma, Chunyan / Wang, Ninghai / Detre, Cynthia / Wang, Guoxing / O'Keeffe, Michael / Terhorst, Cox

The Journal of biological chemistry

2012 Volume 287, Issue 22, Page(s) 18359–18365

Abstract: Phagocytosis is a pivotal process by which macrophages eliminate microorganisms upon recognition by pathogen sensors. Surprisingly, the self-ligand cell surface receptor Slamf1 functions not only as a co-stimulatory molecule but also as a microbial ... ...

Abstract	Phagocytosis is a pivotal process by which macrophages eliminate microorganisms upon recognition by pathogen sensors. Surprisingly, the self-ligand cell surface receptor Slamf1 functions not only as a co-stimulatory molecule but also as a microbial sensor of several Gram-negative bacteria. Upon entering the phagosome of macrophages Slamf1 induces production of phosphatidylinositol 3-phosphate, which positively regulates the activity of the NOX2 enzyme and phagolysosomal maturation. Here, we report that in Escherichia coli-containing phagosomes of mouse macrophages, Slamf1 interacts with the class III PI3K Vps34 in a complex with Beclin-1 and UVRAG. Upon phagocytosis of bacteria the NOX2 activity was reduced in macrophages isolated from Beclin-1(+/-) mice compared with wild-type mice. This Slamf1/Beclin-1/Vps34/UVRAG protein complex is formed in intracellular membrane compartments as it is found without inducing phagocytosis in macrophages, human chronic lymphocytic leukemia cells, and transfectant HEK293 cells. Elimination of its cytoplasmic tail abolished the interaction of Slamf1 with the complex, but deletion or mutation of the two ITAM motifs did not. Both the BD and CCD domains of Beclin-1 were required for efficient binding to Slamf1. Because Slamf1 did not interact with Atg14L or Rubicon, which can also form a complex with Vps34 and Beclin-1, we conclude that Slamf1 recruits a subset of Vps34-associated proteins, which is involved in membrane fusion and NOX2 regulation.
MeSH term(s)	Animals ; Antigens, CD/genetics ; Antigens, CD/physiology ; Apoptosis Regulatory Proteins/genetics ; Beclin-1 ; Cell Line ; Class III Phosphatidylinositol 3-Kinases/genetics ; Humans ; Macrophages/metabolism ; Membrane Fusion/physiology ; Membrane Glycoproteins/metabolism ; Membrane Proteins/genetics ; Mice ; Mice, Knockout ; NADPH Oxidase 2 ; NADPH Oxidases/metabolism ; Phagosomes/metabolism ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/physiology ; Signaling Lymphocytic Activation Molecule Family Member 1 ; Tumor Suppressor Proteins/genetics
Chemical Substances	Antigens, CD ; Apoptosis Regulatory Proteins ; BECN1 protein, human ; Beclin-1 ; Becn1 protein, mouse ; Membrane Glycoproteins ; Membrane Proteins ; Receptors, Cell Surface ; SLAMF1 protein, human ; Slamf1 protein, mouse ; Tumor Suppressor Proteins ; UVRAG protein, human ; UVRAG protein, mouse ; Signaling Lymphocytic Activation Molecule Family Member 1 (169535-43-7) ; CYBB protein, human (EC 1.6.3.-) ; Cybb protein, mouse (EC 1.6.3.-) ; NADPH Oxidase 2 (EC 1.6.3.-) ; NADPH Oxidases (EC 1.6.3.-) ; Class III Phosphatidylinositol 3-Kinases (EC 2.7.1.137)
Language	English
Publishing date	2012-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.367060
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Article ; Online: SLAM family receptors and the SLAM-associated protein (SAP) modulate T cell functions.

Detre, Cynthia / Keszei, Marton / Romero, Xavier / Tsokos, George C / Terhorst, Cox

Seminars in immunopathology

2010 Volume 32, Issue 2, Page(s) 157–171

Abstract: One or more of the signaling lymphocytic activation molecule (SLAM) family (SLAMF) of cell surface receptors, which consists of nine transmembrane proteins, i.e., SLAMF1-9, are expressed on most hematopoietic cells. While most SLAMF receptors serve as ... ...

Abstract	One or more of the signaling lymphocytic activation molecule (SLAM) family (SLAMF) of cell surface receptors, which consists of nine transmembrane proteins, i.e., SLAMF1-9, are expressed on most hematopoietic cells. While most SLAMF receptors serve as self-ligands, SLAMF2 and SLAMF4 use each other as counter structures. Six of the receptors carry one or more copies of a unique intracellular tyrosine-based switch motif, which has high affinity for the single SH2-domain signaling molecules SLAM-associated protein and EAT-2. Whereas SLAMF receptors are costimulatory molecules on the surface of CD4+, CD8+, and natural killer (NK) T cells, they also involved in early phases of lineage commitment during hematopoiesis. SLAMF receptors regulate T lymphocyte development and function and modulate lytic activity, cytokine production, and major histocompatibility complex-independent cell inhibition of NK cells. Furthermore, they modulate B cell activation and memory generation, neutrophil, dendritic cell, macrophage and eosinophil function, and platelet aggregation. In this review, we will discuss the role of SLAM receptors and their adapters in T cell function, and we will examine the role of these receptors and their adapters in X-linked lymphoproliferative disease and their contribution to disease susceptibility in systemic lupus erythematosus.
MeSH term(s)	Animals ; Antigens, CD/genetics ; Antigens, CD/immunology ; Antigens, CD/metabolism ; Cell Differentiation/immunology ; Genetic Predisposition to Disease ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/immunology ; Intracellular Signaling Peptides and Proteins/metabolism ; Lupus Erythematosus, Systemic/genetics ; Lupus Erythematosus, Systemic/immunology ; Lymphocyte Activation/genetics ; Lymphocyte Activation/immunology ; Lymphoproliferative Disorders/genetics ; Lymphoproliferative Disorders/immunology ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/immunology ; Receptors, Cell Surface/metabolism ; Signaling Lymphocytic Activation Molecule Associated Protein ; Signaling Lymphocytic Activation Molecule Family Member 1 ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Antigens, CD ; Intracellular Signaling Peptides and Proteins ; Receptors, Cell Surface ; SH2D1A protein, human ; SLAMF1 protein, human ; Signaling Lymphocytic Activation Molecule Associated Protein ; Signaling Lymphocytic Activation Molecule Family Member 1 (169535-43-7)
Language	English
Publishing date	2010-02-10
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2316828-6
ISSN	1863-2300 ; 1863-2297
ISSN (online)	1863-2300
ISSN	1863-2297
DOI	10.1007/s00281-009-0193-0
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Article: Rafting MHC-II domains in the APC (presynaptic) plasma membrane and the thresholds for T-cell activation and immunological synapse formation.

Gombos, Imre / Detre, Cynthia / Vámosi, György / Matkó, János

Immunology letters

2004 Volume 92, Issue 1-2, Page(s) 117–124

Abstract: Glycosphingolipid- and cholesterol-rich membrane microdomains (rafts) in T-cells are important in triggering and regulation of T(H)-cell activation in immunological synapses (IS), which in turn may control the T-cell repertoire in lymph nodes and at the ... ...

Abstract	Glycosphingolipid- and cholesterol-rich membrane microdomains (rafts) in T-cells are important in triggering and regulation of T(H)-cell activation in immunological synapses (IS), which in turn may control the T-cell repertoire in lymph nodes and at the periphery. It is less known, however, how the "presynaptic side" controls formation and function of IS. We investigated here activation signals and synapse formation frequency of murine IP12-7 T(H) hybridoma cell specific to influenza virus HA-peptide upon stimulation with two B-lymphoma cells, A20 and 2PK3, pulsed with peptide antigen. Confocal microscopic colocalization and FRET data consonantly revealed clustered distribution and constitutive raft-association of a major fraction of MHC-II molecules in both APCs. Costimulatory molecules (CD80 and CD86), not associated constitutively with rafts, were expressed at much lower level in A20 cells. T-cells responded to 2PK3 APC with much higher signal strength than to A20 cells, in good correlation with the frequency of IS formation, as assessed by microscopic conjugation assay. Disruption of rafts by cholesterol depletion in 2PK3 cells largely decreased the magnitude of T(H) cell activation signals, especially at low peptide antigen doses, similarly to masking CD4 with mAb on T-cells. The frequency of IS formation was reduced by blocking LFA-1 on T-cells and CD80 on APCs, by lowering the temperature below the phase transition of the membrane or by disrupting actin cytoskeleton. These data together suggest that the surface density and affinity/stability of peptide-MHC-II complexes and the costimulatory level are primary determinants for an efficient TCR recognition and the strength of the subsequent T-cell signals, as well as of the IS formation, which additionally requires a cytoskeleton-dependent remodeling of APC surface after the initial TCR signal. The threshold of T-cell activation can be further set by rafting MHC-II domains via concentrating high affinity ligands and promoting thereby T-cells for sensing low density antigen. Our data also demonstrate that B-cells, similarly to dendritic cells, could also provide T-cells with antigen-independent weak survival signals, likely associated with integrin engagement.
MeSH term(s)	Animals ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/ultrastructure ; Cell Membrane/immunology ; Histocompatibility Antigens Class II/immunology ; Lymphocyte Activation/immunology ; Lymphoma, B-Cell/immunology ; Membrane Microdomains/immunology ; Mice ; Peptide Fragments/immunology ; T-Lymphocytes/immunology ; Time Factors ; Tumor Cells, Cultured
Chemical Substances	Histocompatibility Antigens Class II ; Peptide Fragments
Language	English
Publishing date	2004-03-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	445150-8
ISSN	1879-0542 ; 0165-2478
ISSN (online)	1879-0542
ISSN	0165-2478
DOI	10.1016/j.imlet.2003.11.022
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Article: Cholesterol and sphingolipids as lipid organizers of the immune cells' plasma membrane: their impact on the functions of MHC molecules, effector T-lymphocytes and T-cell death.

Gombos, Imre / Kiss, Endre / Detre, Cynthia / László, Glória / Matkó, János

Immunology letters

2006 Volume 104, Issue 1-2, Page(s) 59–69

Abstract: The possible regulatory mechanisms by which glycosphingolipid- and cholesterol-rich membrane microdomains, caveolar and non-caveolar lipid rafts, control the immune response are continuously expanding. In the present overview we will focus on how these ... ...

Abstract	The possible regulatory mechanisms by which glycosphingolipid- and cholesterol-rich membrane microdomains, caveolar and non-caveolar lipid rafts, control the immune response are continuously expanding. In the present overview we will focus on how these membrane-organizing lipids are involved, in collaboration with tetraspanin proteins, in the formation of distinct MHC-I and MHC-II microdomains at the cell surface and will analyze the possible roles of MHC compartmentation in the processes of antigen presentation and regulation of various stages of the cellular immune response. Some basic, lipid raft- and tetraspan mediated mechanisms involved in the formation and function of immunological synapses between various APCs and T-cells will also be discussed. Finally, a new aspect of immune regulation by sphingolipids will be briefly described, namely how can the death or stress signals, leading to ceramide accumulation, result in raft-associated regulatory platforms controlling cell death or antigen-induced, TCRmediated signaling of T-lymphocytes. The influence of these signals and their cross-talk on the fate (death or survival) of T-cells and the outcome of T-cell response will also be discussed.
MeSH term(s)	Animals ; Apoptosis ; Cholesterol/analysis ; Cholesterol/metabolism ; Histocompatibility Antigens Class I/immunology ; Histocompatibility Antigens Class II/immunology ; Humans ; Membrane Microdomains/chemistry ; Membrane Microdomains/metabolism ; Sphingolipids/analysis ; Sphingolipids/metabolism ; T-Lymphocytes/immunology
Chemical Substances	Histocompatibility Antigens Class I ; Histocompatibility Antigens Class II ; Sphingolipids ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2006-04-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	445150-8
ISSN	1879-0542 ; 0165-2478
ISSN (online)	1879-0542
ISSN	0165-2478
DOI	10.1016/j.imlet.2005.11.021
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Article ; Online: Glucocorticoid-induced tumor necrosis factor receptor family-related protein regulates CD4(+)T cell-mediated colitis in mice.

Liao, Gongxian / Detre, Cynthia / Berger, Scott B / Engel, Pablo / de Waal Malefyt, Rene / Herzog, Roland W / Bhan, Atul K / Terhorst, Cox

Gastroenterology

2011 Volume 142, Issue 3, Page(s) 582–591.e8

Abstract: Background & aims: The glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR; also called TNFRSF18 or CD357) regulates the T cell-mediated immune response and is present on surfaces of regulatory T (Treg) cells and activated ...

Abstract	Background & aims: The glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR; also called TNFRSF18 or CD357) regulates the T cell-mediated immune response and is present on surfaces of regulatory T (Treg) cells and activated CD4(+) T cells. We investigated the roles of GITR in the development of colitis in mice. Methods: Chronic enterocolitis was induced by the transfer of wild-type or GITR(-/-) CD4(+) T cells to GITR(-/-) × Rag(-/-) or Rag(-/-) mice. We determined the severity of colitis by using the disease activity index; measured levels of inflammatory cytokines, T cells, and dendritic cells; and performed histologic analysis of colon samples. Results: Transfer of nonfractionated CD4(+) cells from wild-type or GITR(-/-) donors induced colitis in GITR(-/-) × Rag(-/-) but not in Rag(-/-) mice. Among mice with transfer-induced colitis, the percentage of Treg and T-helper (Th) 17 cells was reduced but that of Th1 cells increased. Treg cells failed to prevent colitis in GITR(-/-) × Rag(-/-) recipients; this was not the result of aberrant function of GITR(-/-) Treg or T effector cells but resulted from an imbalance between the numbers of tolerogenic CD103(+) and PDCA1(+) plasmacytoid dendritic cells in GITR(-/-) mice. This imbalance impaired Treg cell development and expanded the Th1 population in GITR(-/-) × Rag(-/-) mice following transfer of nonfractionated CD4(+) cells. Conclusions: GITR is not required on the surface of Treg and T effector cells to induce colitis in mice; interactions between GITR and its ligand are not required for induction of colitis. GITR instead appears to control dendritic cell and monocyte development; in its absence, mice develop aggravated chronic enterocolitis via an imbalance of colitogenic Th1 cells and Treg cells.
MeSH term(s)	Animals ; Antigens, CD/metabolism ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/transplantation ; Cell Proliferation ; Cells, Cultured ; Chronic Disease ; Colitis/genetics ; Colitis/immunology ; Colitis/metabolism ; Colitis/pathology ; Colon/immunology ; Colon/metabolism ; Colon/pathology ; Cytokines/metabolism ; Dendritic Cells/immunology ; Disease Models, Animal ; Glucocorticoid-Induced TNFR-Related Protein/deficiency ; Glucocorticoid-Induced TNFR-Related Protein/genetics ; Glucocorticoid-Induced TNFR-Related Protein/metabolism ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Inflammation Mediators/metabolism ; Integrin alpha Chains/metabolism ; Intestinal Mucosa/immunology ; Ligands ; Lymph Nodes/immunology ; Lymphocyte Transfusion ; Macrophages/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Severity of Illness Index ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; T-Lymphocyte Subsets/transplantation ; T-Lymphocytes, Regulatory/immunology ; Th1 Cells/immunology ; Th17 Cells/immunology ; Time Factors
Chemical Substances	Antigens, CD ; Cytokines ; Glucocorticoid-Induced TNFR-Related Protein ; Homeodomain Proteins ; Inflammation Mediators ; Integrin alpha Chains ; Ligands ; Tnfrsf18 protein, mouse ; alpha E integrins ; RAG-1 protein (128559-51-3)
Language	English
Publishing date	2011-12-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2011.11.031
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Article ; Online: Expansion of an osteopontin-expressing T follicular helper cell subset correlates with autoimmunity in B6.Sle1b mice and is suppressed by the H1-isoform of the Slamf6 receptor.

Keszei, Marton / Detre, Cynthia / Castro, Wilson / Magelky, Erica / O'Keeffe, Michael / Kis-Toth, Katalin / Tsokos, George C / Wang, Ninghai / Terhorst, Cox

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2013 Volume 27, Issue 8, Page(s) 3123–3131

Abstract: The costimulatory receptor Slamf6 partially controls lupus-related autoimmunity in congenic Sle1b mice; for instance, the presence of the protein isoform Slamf6-H1 in Sle1b.Slamf6-H1 mice mitigates disease. Here, we report that young Sle1b mice, but not ... ...

Abstract	The costimulatory receptor Slamf6 partially controls lupus-related autoimmunity in congenic Sle1b mice; for instance, the presence of the protein isoform Slamf6-H1 in Sle1b.Slamf6-H1 mice mitigates disease. Here, we report that young Sle1b mice, but not Sle1b.Slamf6-H1 or B6 mice, contain a memory T-helper cell subset identified by ]mt]2-fold increase in expression of 17 genes, chief among which is Spp1, encoding the cytokine osteopontin (OPN). These T follicular helper (TFH) cells, including OPN(+) TFH cells, expand concomitantly with severity of the disease. By contrast, Sle1b.Slamf6-H1 or Sle1b.SAP(-)/(-) mice do not develop autoantibodies and the number of T(FH) cells is 5 times lower than in age-matched Sle1b mice. By comparing Sle1b and Sle1b.OPN(-)/(-) mice, we find that the lack of OPN expression impedes early autoantibody production. Furthermore, on the adoptive transfer of Sle1b.OPN(-)/(-) CD4(+) T cells into bm12 recipients autoantibody production and germinal center formation is reduced compared to recipients of Sle1b.OPN(+/+) CD4(+) T cells. We propose a model in which OPN provides a survival signal for a precursor T(FH) cell subset, which is a key factor in autoimmunity.
MeSH term(s)	Animals ; Antigens, CD/genetics ; Antigens, CD/immunology ; Antigens, CD/metabolism ; Antigens, Differentiation/genetics ; Antigens, Differentiation/immunology ; Antigens, Differentiation/metabolism ; Autoimmunity/genetics ; Autoimmunity/immunology ; Blotting, Western ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Cell Proliferation ; Female ; Flow Cytometry ; Lupus Erythematosus, Systemic/genetics ; Lupus Erythematosus, Systemic/immunology ; Lupus Erythematosus, Systemic/metabolism ; Male ; Mice ; Mice, Knockout ; Osteopontin/genetics ; Osteopontin/immunology ; Osteopontin/metabolism ; Programmed Cell Death 1 Receptor ; Protein Isoforms/genetics ; Protein Isoforms/immunology ; Protein Isoforms/metabolism ; Receptors, CXCR5/genetics ; Receptors, CXCR5/immunology ; Receptors, CXCR5/metabolism ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/immunology ; Receptors, Cell Surface/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signaling Lymphocytic Activation Molecule Family ; Signaling Lymphocytic Activation Molecule Family Member 1 ; T-Lymphocytes, Helper-Inducer/cytology ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/metabolism ; Transcriptome/immunology
Chemical Substances	Antigens, CD ; Antigens, Differentiation ; CXCR5 protein, mouse ; Pdcd1 protein, mouse ; Programmed Cell Death 1 Receptor ; Protein Isoforms ; Receptors, CXCR5 ; Receptors, Cell Surface ; Signaling Lymphocytic Activation Molecule Family ; Slamf6 protein, mouse ; Osteopontin (106441-73-0) ; Signaling Lymphocytic Activation Molecule Family Member 1 (169535-43-7)
Language	English
Publishing date	2013-04-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.12-226951
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Article ; Online: Wiskott-Aldrich syndrome protein (WASP) and N-WASP are critical for peripheral B-cell development and function.

Westerberg, Lisa S / Dahlberg, Carin / Baptista, Marisa / Moran, Christopher J / Detre, Cynthia / Keszei, Marton / Eston, Michelle A / Alt, Frederick W / Terhorst, Cox / Notarangelo, Luigi D / Snapper, Scott B

Blood

2012 Volume 119, Issue 17, Page(s) 3966–3974

Abstract: The Wiskott-Aldrich syndrome protein (WASP) is a key cytoskeletal regulator of hematopoietic cells. Although WASP-knockout (WKO) mice have aberrant B-cell cytoskeletal responses, B-cell development is relatively normal. We hypothesized that N-WASP, a ... ...

Abstract	The Wiskott-Aldrich syndrome protein (WASP) is a key cytoskeletal regulator of hematopoietic cells. Although WASP-knockout (WKO) mice have aberrant B-cell cytoskeletal responses, B-cell development is relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homolog of WASP, may serve some redundant functions with WASP in B cells. In the present study, we generated mice lacking WASP and N-WASP in B cells (conditional double knockout [cDKO] B cells) and show that cDKO mice had decreased numbers of follicular and marginal zone B cells in the spleen. Receptor-induced activation of cDKO B cells led to normal proliferation but a marked reduction of spreading compared with wild-type and WKO B cells. Whereas WKO B cells showed decreased migration in vitro and homing in vivo compared with wild-type cells, cDKO B cells showed an even more pronounced decrease in the migratory response in vivo. After injection of 2,4,6-trinitrophenol (TNP)-Ficoll, cDKO B cells had reduced antigen uptake in the splenic marginal zone. Despite high basal serum IgM, cDKO mice mounted a reduced immune response to the T cell-independent antigen TNP-Ficoll and to the T cell-dependent antigen TNP-keyhole limpet hemocyanin. Our results reveal that the combined activity of WASP and N-WASP is required for peripheral B-cell development and function.
MeSH term(s)	Animals ; B-Lymphocytes/cytology ; B-Lymphocytes/physiology ; Blotting, Western ; Cell Movement ; Cell Proliferation ; Cells, Cultured ; Chemotaxis ; Ficoll/analogs & derivatives ; Ficoll/pharmacology ; Flow Cytometry ; Hematopoiesis/physiology ; Immunization ; Immunoenzyme Techniques ; Integrases/metabolism ; Mice ; Mice, Knockout ; Trinitrobenzenes/pharmacology ; Wiskott-Aldrich Syndrome Protein/physiology ; Wiskott-Aldrich Syndrome Protein, Neuronal/physiology
Chemical Substances	TNP-ficoll ; Trinitrobenzenes ; Was protein, mouse ; Wasl protein, mouse ; Wiskott-Aldrich Syndrome Protein ; Wiskott-Aldrich Syndrome Protein, Neuronal ; Ficoll (25702-74-3) ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
Language	English
Publishing date	2012-03-12
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2010-09-308197
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