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  • 1
    Abstract: The existence and expansion of adaptive NK-cell subsets have been linked to HCMV infection. Phenotypically, a majority of adaptive NK cells expresses the activating receptor NKG2C and CD57. Some of the molecular factors driving the expansion of NKG2C+ CD57+ NK cells in HCMV infection have been identified. The direct interaction of adaptive NK cells with HCMV-infected cells, preceding the expansion, however, remains less studied. Recently, adaptive NK cells were reported to express higher levels of the co-activating receptor CD2. We explored whether CD2 was directly involved in the response of adaptive NK cells to HCMV. In a co-culture system of human PBMCs and productively infected fibroblasts, we observed an upregulation of CD69, CD25, and HLA-DR on all NK cells. However, only in adaptive NK cells was this increase largely blocked by antibodies against CD2 and CD58. Functionally, this blockade also resulted in diminished production of IFN-gamma and TNF-alpha by adaptive human NK cells in response to HCMV-infected cells. Our results demonstrate that binding of CD2 to upregulated CD58 on infected cells is a critical event for antibody-mediated activation and subsequent effector functions of adaptive NKG2C+ CD57+ NK cells during the antiviral response.
    Type of Publication: Journal article published
    PubMed ID: 27469079
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  • 2
    Abstract: Activation of the C-type lectin receptor Dectin-1 by beta-glucans triggers multiple signals within DCs that result in activation of innate immunity. While these mechanisms can potently prime CD8+ cytotoxic T-cell (CTL) responses without additional adjuvants, the Dectin-1 effector pathways that control CTL induction remain unclear. Here we demonstrate that Dectin-1-induced CTL cross-priming in mice does not require inflammasome activation but strictly depends on the adapter protein Card9 in vitro. In vivo, Dectin-1-mediated Card9 activation after vaccination drives both expansion and activation of Ag-specific CTLs, resulting in long-lasting CTL responses that are sufficient to protect mice from tumor challenge. This Dectin-1-induced antitumor immune response was independent of NK cell function and completely abrogated in Card9-deficient mice. Thus, our results demonstrate that Dectin-1-triggered Card9 signaling but not inflammasome activation can potently cross-prime Ag-specific CTLs, suggesting that this pathway would be a candidate for immunotherapy and vaccine development.
    Type of Publication: Journal article published
    PubMed ID: 28295265
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  • 3
  • 4
    Abstract: Antigen-specific T cells isolated from healthy individuals (HIs) have shown great therapeutic potential upon adoptive transfer for the treatment of viremia in immunosuppressed patients. The lack of comprehensive data on the prevalence and characteristics of leukemia-associated antigen (LAA)-specific T cells in HIs still limits such an approach for tumor therapy. Therefore, we have investigated T-cell responses against prominent candidates comprising Wilms' tumor protein 1 (WT1), preferentially expressed antigen in melanoma (PRAME), Survivin, NY-ESO, and p53 by screening PBMCs from HIs using intracellular IFN-gamma staining following provocation with LAA peptide mixes. Here, we found predominantly poly-functional effector/effector memory CCR7(-) /CD45RA(+/-) /CD8(+) LAA peptide-specific T cells with varying CD95 expression in 34 of 100 tested HIs, whereas CD4(+) T cells responses were restricted to 5. Most frequent LAA peptide-specific T cell responses were directed against WT1 and PRAME peptides with a prevalence of 20 and 17%, respectively, showing the highest magnitude (0.16% +/- 0.22% (mean +/- SD)) for PRAME peptides. Cytotoxicity of PRAME peptide-specific T cells was demonstrated by specific killing of PRAME peptide-pulsed T2 cells. Furthermore, the proliferative capacity of PRAME peptide-specific T cells was confined to HIs responsive toward PRAME peptide challenge corroborating the accuracy of the screening results. In conclusion, we identified PRAME as a promising target antigen for adoptive leukemia therapy.
    Type of Publication: Journal article published
    PubMed ID: 29738081
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  • 5
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; IRRADIATION ; proliferation ; SURVIVAL ; CELL ; COMBINATION ; IN-VIVO ; VIVO ; GENERATION ; PROTEIN ; PROTEINS ; transcription ; MICE ; ACTIVATION ; DNA ; TRANSCRIPTION FACTOR ; ANTIGEN ; T cell ; T cells ; T-CELL ; T-CELLS ; BINDING ; PHOSPHORYLATION ; CELL-SURVIVAL ; ELEMENT ; ELEMENT-BINDING PROTEIN ; knockout ; MUTANT ; NO ; TRANSCRIPTION FACTORS ; TRANSGENIC MICE ; PROMOTER ; transgenic ; RESPONSIVE ELEMENT ; T lymphocyte ; OVEREXPRESSION ; rodent ; T lymphocytes ; BINDING PROTEIN ; thymus ; BINDING-PROTEIN ; IL-2 PRODUCTION ; MOLECULAR-BASIS
    Abstract: Recent generation of genetically modified Creb1 mutant mice has revealed an important role for CREB (CAMP responsive element binding protein) and the related proteins CREM (CAMP responsive element modulator) and ATF1 (activating transcription factor 1) in cell survival, in agreement with previous studies using overexpression of dominant-negative CREB (dnCREB). CREB and ATF1 are abundantly expressed in T cells and are rapidly activated by phosphorylation when T cells are stimulated through the T cell antigen receptor. We show that T cell-specific loss of CREB in mice, in combination with the loss of ATF1, results in reduced thymic cellularity and delayed thymic recovery following sublethal irradiation but no changes in T cell development or activation. These data show that loss of CREB function has specific effects on thymic T lymphocyte proliferation and homeostasis in vivo
    Type of Publication: Journal article published
    PubMed ID: 15214044
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  • 6
    Keywords: CELLS ; IN-VITRO ; proliferation ; SURVIVAL ; BLOOD ; CELL-PROLIFERATION ; Germany ; human ; SYSTEM ; DISEASE ; PROTEIN ; COMPONENTS ; PATIENT ; ACTIVATION ; RESPONSES ; AUTOIMMUNE-DISEASE ; T-CELL ; T-CELLS ; SUPPRESSION ; FREQUENCY ; IMMUNE-RESPONSES ; GLYCOPROTEIN ; NERVOUS-SYSTEM ; resistance ; LYMPHOCYTES ; PHENOTYPE ; INDIVIDUALS ; IMMUNE-RESPONSE ; T-LYMPHOCYTES ; CENTRAL-NERVOUS-SYSTEM ; HEALTHY ; inflammation ; rodent ; T lymphocytes ; INTERLEUKIN-2 ; myelin oligodendrocyte glycoprotein ; AUTOIMMUNITY ; DISORDERS ; RECOMBINANT ; SUBSET ; RHEUMATOID-ARTHRITIS ; FOXP3 ; FUNCTIONAL-CHARACTERIZATION ; cell proliferation ; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ; LEVEL ; protein A ; ABILITY ; human CD4(+)CD25(high) regulatory T cells ; multiple sclerosis ; Myelin ; POTENCY ; rodents
    Abstract: Immunoregulatory T cells of CD4(+)CD25(+) phenotype suppress T cell function and protect rodents from organ-specific autoimmune disease. The human counterpart of this subset of T cells expresses high levels of CD25 and its role in human autoimmune disorders is currently under intense investigation. In multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), the activation of circulating self-reactive T cells with specificity for myelin components is considered to be an important disease initiating event. Here, we investigated whether MS is associated with an altered ability of CD4(+)CD25(high) regulatory T cells (T-reg) to confer suppression of myelin-specific immune responses. Whereas T-reg frequencies were equally distributed in blood and cerebrospinal fluid of MS patients and did not differ compared to healthy controls, the suppressive potency of patient-derived CD4(+)CD25(high) T lymphocytes was impaired. Their inhibitory effect on antigen-specific T cell proliferation induced by human recombinant myelin oligodendrocyte protein as well as on immune responses elicited by polyclonal and allogeneic stimuli was significantly reduced compared to healthy individuals. The effect was persistent and not due to responder cell resistance or altered survival of T-reg, suggesting that a defective immunoregulation of peripheral T cells mediated by CD4(+)CD25(high) T lymphocytes promotes CNS autoimmunity in MS
    Type of Publication: Journal article published
    PubMed ID: 16206232
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  • 7
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; proliferation ; CELL ; human ; INHIBITION ; THERAPY ; GENERATION ; SYSTEM ; SYSTEMS ; TOOL ; DISEASE ; DISEASES ; POPULATION ; transcription ; TISSUE ; MICE ; INFECTION ; MECHANISM ; TRANSCRIPTION FACTOR ; MARKER ; ANTIGEN ; T cell ; T cells ; T-CELLS ; INJECTION ; BIOLOGY ; IDENTIFICATION ; LYMPHOMA ; MALIGNANCIES ; HUMANS ; NUMBER ; MARKERS ; LYMPHOCYTES ; CANCER-CELLS ; POPULATIONS ; IMMUNE-RESPONSE ; IMMUNOTHERAPY ; REJECTION ; TARGETS ; FUTURE ; INFECTIONS ; CELL-SURFACE ; CANCER-THERAPY ; MALIGNANCY ; cancer therapy ; AUTOIMMUNE-DISEASES ; FOXP3 ; LEVEL ; LYMPHOMAS ; graft-versus-host disease ; function ; TRANSCRIPTION FACTOR FOXP3 ; IMMUNOLOGICAL SELF-TOLERANCE ; autoimmune disease ; COMMUNITY ; cure ; DEPLETION ; regulatory T cells
    Abstract: Regulatory T cells (Treg) provide protection from autoimmune disease, graft-versus-host disease, transplant rejection and overwhelming tissue destruction during infections. Conversely, high Treg numbers enable cancer cells to evade the host immune response. Thus, Treg are seen as an important tool to manipulate the immune response. However, as the immunological community is trying to move this knowledge from mice to humans, contradictory results regarding the number and function of Treg in various diseases are appearing. This problem arises because we cannot clearly define Treg populations on the basis of expression of CD25 and other cell surface markers in humans. This review addresses the utility of the FOXP3 forkhead transcription factor for the identification of Treg populations and summarizes recent data on the expression of FOXP3 in lymphomas. It is crucial to really understand Treg biology before attempting therapies, including (i) the injection of expanded Treg to cure autoimmune disease or prevent graft-versus-host disease or (ii) the depletion or inhibition of Treg in cancer therapy. For instance, new data arising from the study of haematological malignancies highlight the additional complexity of systems where malignant cell populations may also be direct Treg targets
    Type of Publication: Journal article published
    PubMed ID: 17051620
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  • 8
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; IN-VIVO ; KINASE ; MODEL ; PATHWAY ; PATHWAYS ; VIVO ; SYSTEM ; DISEASE ; ADHESION MOLECULES ; MONOCLONAL-ANTIBODY ; MICE ; ACTIVATION ; COMPLEX ; LIGAND ; COMPLEXES ; T cell ; T cell activation ; T-CELL ; BINDING ; signal transduction ; ASSOCIATION ; resistance ; SIGNAL-TRANSDUCTION ; LYMPHOCYTES ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; ADHESION ; MIGRATION ; COMPLEX-FORMATION ; rodent ; C3H/HEJ MICE ; LIGAND-BINDING ; CD44 ; signaling ; RE ; SURFACE GLYCOPROTEIN ; DELAYED-TYPE HYPERSENSITIVITY ; alopecia areata ; function ; lymph node ; LYMPH-NODE ; PROLIFERATIVE ACTIVITY ; focal adhesion kinase ; CYTOPLASMIC DOMAIN ; in vivo ; AA ; autoimmune disease ; MOTILITY ; ACCESS ; PROGRESS ; ALOPECIA-AREATA ; allergy autoimmunity ; PREVENTS APOPTOSIS ; SRC-FAMILY KINASES
    Abstract: CD44 is involved in leukocyte migration and activation and has recently been reported to contribute to leukocyte extravasation by associating with CD49d. We explored whether similar changes in CD44 activity are seen in vivo using murine alopecia areata (AA) as a chronic, organ-related autoimmune disease model system. Expression of the activated, hyaluronan-binding form of CD44, and of CD49d, was elevated in draining lymph node cells (LNC) of AA-affected mice as compared to control mice. LNC of AA mice displayed increased motility, proliferative activity and apoptosis resistance, which were equally well inhibited by anti-CD44 and anti-CD49d. The latter is the sequelae of the association between CD44 and CD49d that is seen in activated lymphocytes. Significantly, due to CD44-CD49d complex formation, CD44 gains access to focal adhesion kinase and CD49d gains access to CD44-associated Ick and ezrin, such that downstream kinases become activated via CD44 or CD49d engagement. Thus, by their association, CD44 and CD49d mutually avail themselves of the partner's signaling pathways and the ligand binding of each one triggers signaling pathways of both. This strongly influences the lymphocytes' activation state and function
    Type of Publication: Journal article published
    PubMed ID: 17039568
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  • 9
    Keywords: CELLS ; ENDOTHELIAL-CELLS ; CELL ; Germany ; IN-VIVO ; MODEL ; MODELS ; VIVO ; MICE ; LIGAND ; FAMILY ; CONTRAST ; BINDING ; treatment ; MOLECULE ; ALPHA ; ACID ; GLYCOPROTEIN ; ADHESION ; MUSCLE ; FRAGMENTS ; LECTIN ; INTERACTS ; P-SELECTIN ; CHILDREN ; TNF-ALPHA ; inflammation ; C-type lectin ; NEUTROPHILS ; FAMILIES ; RESIDUES ; DEFICIENT MICE ; carbohydrate structures ; GLYCOPROTEINS ; INTEGRINS ; function ; in vivo ; FRAGMENT ; ENDOTHELIAL-CELL ; carbohydrate ; ACID-RESIDUES ; GLYCOPROTEIN LIGAND-1 ; HIGH ENDOTHELIAL VENULES ; LYMPHOCYTE RECIRCULATION ; ROLLING IN-VIVO ; TYROSINE SULFATION
    Abstract: L-selectin belongs to the C-type lectin family of glycoproteins and is constitutively expressed on most leukocytes. L-selectin mediates leukocyte rolling in inflamed microvessels and high endothelial venules (HEV) via binding to specific carbohydrate structures on selectin ligands. Previous studies using sialidase treatment suggested a role of sialic acid residues in L-selectin-dependent rolling. To investigate the role of the alpha 2,3-sialyltransferase (ST3Gal)-IV on L-selectin ligand activity in vivo, we studied leukocyte rolling in inflamed venules of the cremaster muscle and in Peyer's patch HEV of ST3Gal-IV-deficient mice and littermate control mice. In cremaster muscle venules with or without TNF-alpha treatment, L-selectin-dependent rolling was almost completely abolished in ST3Gal-IV-/- mice. In both models, L-selectin interacts with P-selectin glycoprotein ligand-1 (PSGL-1) presented by adherent leukocytes and leukocyte fragments, but not with endothelial L-selectin ligands. In contrast, L-selectin-dependent rolling in Peyer's patch HEV, which is mediated by unknown endothelial L-selectin ligands, was not impaired in the absence of ST3Gal-IV. Our in vivo data show that PSGL-1, the molecule responsible for L-selectin-mediated leukocyte interactions in inflammation, is dependent on ST3Gal-IV, while alpha 2,3-sialylation by ST3Gal-IV is not necessary for L-selectin ligand activity on high endothelial cells of Peyer's patch HEV
    Type of Publication: Journal article published
    PubMed ID: 17111351
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  • 10
    Keywords: CANCER ; CELLS ; CELL ; Germany ; THERAPY ; ACTIVATION ; RECOGNITION ; NATURAL-KILLER-CELLS ; NK cells ; RECEPTORS ; CANCER-THERAPY ; education ; CYTOTOXICITY ; CLASS-I MOLECULES ; THERAPIES ; cancer therapy ; immunology ; - ; DAP12
    Type of Publication: Journal article published
    PubMed ID: 17447232
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