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Dieter Kabelitz

Publications and source records attributed to Dieter Kabelitz.

At least 19 recordsLinked to original sources
PubMed2007

Perspectives of gammadelta T cells in tumor immunology.

Subsets of human gammadelta T cells recognize tumor cell-expressed ligands that are not seen by the T-cell receptor of conventional alphabeta T cells. Vdelta1 T cells recognize MHC class I chain-related molecules A and B and UL-16-binding proteins expressed at variable levels on epithelial tumor cells and some leukemias and lymphomas. In addition, therapeutically used aminobisphosphonates and synthetic phosphoantigens activate Vdelta2 T cells, the dominant subset of gammadelta T cells in human peripheral blood that display strong cytotoxicity towards various epithelial tumors. Intentional activation of gammadelta T cells in vivo and/or adoptive cell therapy with in vitro expanded gammadelta T cells holds considerable promise as a novel immunotherapy in certain types of cancer.

Antigens, Neoplasm↗
PubMed2006

Expression and function of Toll-like receptors in T lymphocytes.

Toll-like receptors (TLRs) are widely expressed in the innate immune system. They recognize conserved microbial ligands such as bacterial lipopolysaccharide, lipopeptides or viral and bacterial RNA and DNA. TLRs play an essential role in innate immune responses and in the initiation of adaptive immune responses. However, certain TLRs are also expressed in T lymphocytes, and the respective ligands can directly modulate T cell function. TLR2, TLR3, TLR5 and TLR9 act as co-stimulatory receptors to enhance proliferation and/or cytokine production of T-cell receptor-stimulated T lymphocytes. In addition, TLR2, TLR5 and TLR8 modulate the suppressive activity of naturally occurring CD25(+)CD4(+) regulatory T cells. The direct responsiveness of T lymphocytes to TLR ligands offers new perspectives for the immunotherapeutic manipulation of T cell responses.

Animals↗
PubMed2006

Secretory lysosomes and their cargo in T and NK cells.

Secretory lysosomes are specialized organelles that combine catabolic functions of conventional lysosomes with an inducible secretory potential. They are present in various hematopoietic cell types commonly characterized by the need for rapid mobilization and secretion of effector proteins. As an example, the cytotoxic effector function of T cells and natural killer cells strictly depends on the activation-dependent mobilization of such vesicles to the cytotoxic immunological synapse. This review focuses on some molecules that have been identified as cargo of secretory lysosomes and which play a major role in effector function of CTL and NK cells. We also briefly point to the fact that the dysregulation of formation and transport of secretory vesicles is causative for severe immunodeficiencies and autoimmunity observed in patients and also in mice that have been used as representative model systems to analyze the pathophysiological relevance of secretory vesicles in vivo.

Animals↗
PubMed2006

Inhibition of TNF receptor 1 internalization by adenovirus 14.7K as a novel immune escape mechanism.

The adenoviral protein E3-14.7K (14.7K) is an inhibitor of TNF-induced apoptosis, but the molecular mechanism underlying this protective effect has not yet been explained exhaustively. TNF-mediated apoptosis is initiated by ligand-induced recruitment of TNF receptor-associated death domain (TRADD), Fas-associated death domain (FADD), and caspase-8 to the death domain of TNF receptor 1 (TNFR1), thereby establishing the death-inducing signaling complex (DISC). Here we report that adenovirus 14.7K protein inhibits ligand-induced TNFR1 internalization. Analysis of purified magnetically labeled TNFR1 complexes from murine and human cells stably transduced with 14.7K revealed that prevention of TNFR1 internalization resulted in inhibition of DISC formation. In contrast, 14.7K did not affect TNF-induced NF-kappaB activation via recruitment of receptor-interacting protein 1 (RIP-1) and TNF receptor-associated factor 2 (TRAF-2). Inhibition of endocytosis by 14.7K was effected by failure of coordinated temporal and spatial assembly of essential components of the endocytic machinery such as Rab5 and dynamin 2 at the site of the activated TNFR1. Furthermore, we found that the same TNF defense mechanisms were instrumental in protecting wild-type adenovirus-infected human cells expressing 14.7K. This study describes a new molecular mechanism implemented by a virus to escape immunosurveillance by selectively targeting TNFR1 endocytosis to prevent TNF-induced DISC formation.

Adenoviridae↗
PubMed2006

The murine TRAIL receptor signals caspase-independent cell death through ceramide.

Death receptors such as the 55 kDa tumor necrosis factor (TNF) receptor (TNF-R55) or Fas can initiate both apoptotic (caspase-dependent) and caspase-independent routes to programmed cell death (PCD). Here, we demonstrate for the first time that the single murine receptor for (TNF)-related apoptosis-inducing ligand (mTRAIL-R2) can induce a caspase-independent form of PCD with necrosis-like features in addition to apoptosis. Analysis of morphological and cellular features of caspase-independent PCD in response to TRAIL and TNF suggests that mTRAIL-R2 and TNF-R55 elicit caspase-independent PCD through similar pathways, although without participation of cathepsins. Cells overexpressing acid ceramidase (AC), an enzyme that metabolizes the sphingolipid ceramide, show enhanced survival from TRAIL-induced caspase-independent PCD but not from apoptosis, implicating a function of ceramide as a key mediator in caspase-independent PCD (but not apoptosis) induced by mTRAIL-R2. In concert with the enhanced resistance of AC-overexpressing cells against caspase-independent PCD induced by TNF, our results suggest that ceramide acts as a common mediator of caspase-independent PCD caused by death receptors such as mTRAIL-R2 and TNF-R55.

Animals↗
PubMed2006

Identification of HLA-A*0201-presented T cell epitopes derived from the oncofetal antigen-immature laminin receptor protein in patients with hematological malignancies.

The oncofetal Ag immature laminin receptor (OFA-iLR) is a potential target molecule for immunotherapeutic studies in several tumor entities, including hematological malignancies. In the present study, we characterize two HLA-A*0201-presented epitopes eliciting strong OFA-iLR peptide-specific human cytotoxic T cell (CTLs) responses in vitro. Both allogeneic HLA-A*0201-matched and autologous CTLs recognized and killed endogenously OFA-iLR-expressing tumor cell lines and primary malignant cells from patients with hemopoietic malignancies in an MHC-restricted fashion but spared nonmalignant hemopoietic cells. Spontaneous OFA-iLR peptide-specific T cell reactivity was detectable in a significant proportion of leukemia patients. Interestingly, in patients with chronic lymphocytic leukemia and multiple myeloma but not in those with acute myeloid leukemia, significant frequencies of OFA peptide-specific CTLs could be detected in an early stage of disease but disappeared in patients with progressive disease. The identification of OFA-iLR-derived peptide epitopes provides a basis for tumor immunological studies and therapeutic vaccination strategies in patients with OFA-iLR-expressing malignancies.

Adult↗
PubMed2006

TCR trans-rearrangements: biological significance in antigen recognition vs the role as lymphoma biomarker.

V(D)J rearrangements occur within loci of TCR and BCR genes, thus generating the diversity of the AgR repertoire. In addition, interlocus V(D)J rearrangements occur, giving rise to so-called "trans-rearrangements." Such trans-rearrangements increase the diversity of the immune receptor repertoire and can be expressed as functional chimeric TCR proteins on the surface of T cells. Although chimeric receptors are not pathogenic per se, the frequency of AgR trans-rearrangements correlates with the level of genetic instability and thus could be used as a predictive biomarker for lymphoma risk.

Animals↗
PubMed2006

The adaptor protein Nck interacts with Fas ligand: Guiding the death factor to the cytotoxic immunological synapse.

The Fas ligand (FasL) is a key death factor of cytotoxic T lymphocytes and natural killer cells. It is stored intracellularly as a transmembrane protein of secretory lysosomes. Upon activation, these vesicles are transported to the cytotoxic immunological synapse (IS), and FasL becomes exposed to the cell surface to trigger cell death through ligation of its receptor Fas (CD95) on the target cell. We propose that the FasL-associated adaptor protein Nck is involved in the actin-dependent transport of FasL-bearing secretory lysosomes to the IS. Nck binds to the proline-rich portion of FasL and alters its subcellular distribution when coexpressed in 293T cells. In T lymphocytes, endogenous Nck partially colocalizes with lysosome-associated FasL. When T cell clones or lines are exposed to target cells, both proteins and other components of secretory lysosomes (i.e., granzyme B or cathepsin D) are transported to the cell-cell interface. The present data suggest that T cell receptor engagement provokes a rapid, tyrosine kinase- and actin-dependent transport of Nck-associated FasL-carrying lysosomes to the contact area. Our observations support the previous notion that the unique cytoplasmic tail of FasL is crucial for its directed transport to the cell surface and into the assembling cytotoxic IS.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Differential expression of CD126 and CD130 mediates different STAT-3 phosphorylation in CD4+CD25- and CD25high regulatory T cells.

IL-6 is a pleiotropic cytokine involved in T-lymphocyte biology. Following IL-6 binding, the soluble IL-6R (CD126)-IL-6 complex can directly activate cells that express the signal-transducing gp130 (CD130) molecule, which mediates two distinct signals, mitogenesis by mitogen-activated protein kinase (MAPK) activation and anti-apoptosis by signal transducer and activator of transcription 3 (STAT-3) activation. This 'trans-signaling', also mediated by the soluble CD126/IL-6 fusion protein hyper-IL-6 (H-IL-6), contributes to the perpetuation of autoimmune diseases such as Morbus Crohn or rheumatoid arthritis. On the other hand, the homeostasis of cellular immune reactions and its failure leading to autoimmune diseases are critically controlled by regulatory T cells (Tregs). Here, we investigated the differential expression of CD126 and CD130 on subsets of human leukocytes in blood, tonsil and spleen. Among CD4+ T cells, differential expression of CD126 and CD130 was observed on the basis of CD25 expression. CD4+CD25- T cells were strongly CD126+ and CD130+, whereas CD25(high) Tregs expressed CD126 but little CD130. Both CD126 and CD130 were down-modulated on CD4+CD25- T cells following ligand binding, whereas only marginal modulation was observed on Tregs. Interestingly, we observed a correlation between CD126 and CD130 expression with STAT-3 phosphorylation in CD4+CD25- T cells compared with Tregs after stimulation with IL-6 or H-IL-6, whereas the MAPK extracellular signal-regulated kinase 1/2 were not activated by CD130 dimerization. The differential expression of CD126 and CD130 and subsequent STAT-3 phosphorylation might be relevant for the recently described role of IL-6 in the control of Treg activity.

Blotting, Western↗
PubMed2006

Direct costimulatory effect of TLR3 ligand poly(I:C) on human gamma delta T lymphocytes.

TLR3 recognizes viral dsRNA and its synthetic mimetic polyinosinic-polycytidylic acid (poly(I:C)). TLR3 expression is commonly considered to be restricted to dendritic cells, NK cells, and fibroblasts. In this study we report that human gammadelta and alphabeta T lymphocytes also express TLR3, as shown by quantitative real-time PCR, flow cytometry, and confocal microscopy. Although T cells did not respond directly to poly(I:C), we observed a dramatic increase in IFN-gamma secretion and an up-regulation of CD69 when freshly isolated gammadelta T cells were stimulated via TCR in the presence of poly(I:C) without APC. IFN-gamma secretion was partially inhibited by anti-TLR3 Abs. In contrast, poly(I:C) did not costimulate IFN-gamma secretion by alphabeta T cells. These results indicate that TLR3 signaling is differentially regulated in TCR-stimulated gammadelta and alphabeta T cells, suggesting an early activation of gammadelta T cells in antiviral immunity.

Cell Line↗
PubMed2006

Transfusion-related risks of intradermal allogeneic lymphocyte immunotherapy: single cases in a large cohort and review of the literature.

PROBLEM: Lymphocyte immunotherapy (LIT) is applied in infertility treatment. Moreover, it has been suggested for prevention of rhesus D-hemolytic disease and as a vaccine for reduction of human immunodeficiency virus-1 susceptibility. Although transfusion-related problems have been rarely reported they were a matter of debate. Here we discuss extensive single-center experience with intradermal LIT for implantation failure and recurrent miscarriages. METHOD OF STUDY: Retrospective 2- to 3-year follow-up of in vitro fertilization couples treated during 1996-2002 (feedback 2,848/3,041 = 93%), registering 930 deliveries. Prospective survey for acute reactions for 2000-2003 (feedback 2,687/3,246 = 83%). Review of the literature. RESULTS: Infections of the patient and transplant rejection later in life are minor residual risks. Post-transfusion purpura was suspected once but not verified. Anaphylaxis or malignancy were not promoted. Fetal/newborn alloimmune disease (severe hemolytic disease, thrombocytopenia, neutropenia) were not observed. CONCLUSION: Based on microbiological, immunological, and hematological testing the risks of intradermal LIT are low.

Abortion, Habitual↗
PubMed2006

Regulation of regulatory T cells: role of dendritic cells and toll-like receptors.

Regulatory T cells (Treg) are characterized by high-level surface CD25 and intracellular FoxP3 expression. Treg are instrumental in the maintenance of peripheral immune tolerance and the control of adaptive immune responses. Naturally occuring Treg suppress T-cell responses by cell contact-dependent mechanisms, whereas induced regulatory cells, including Tr1 cells, secrete inhibitory cytokines such as transforming growth factor (TGF)-beta and interleukin-10. The interplay between Treg and antigen-responsive T cells is modulated by dendritic cells (DC). Whereas immature myeloid precursors of DC suppress T-cell activation per se and immature DC support Treg development, mature DC can override Treg-mediated suppression in vitro and in vivo. Mature DC activated through Toll-like receptor (TLR) pattern recognition receptors produce proinflammatory cytokines, including interleukin-6, which render responder T cells refractory to the suppressive effect of Treg. In addition, Treg also express certain TLR, and the activation and/or suppressor function of Treg is modulated directly by the respective ligands. In this review, we discuss current models of how signals delivered through innate immune receptors in response to pathogen-associated molecular patterns affect adaptive immune responses via modulation of Treg function.

Animals↗
PubMed2005

Regulation of FasL expression: a SH3 domain containing protein family involved in the lysosomal association of FasL.

As a death factor of T cells and Natural Killer (NK) cells, Fas Ligand (FasL) is stored in association with secretory lysosomes. Upon stimulation, these cytotoxic granules are transported to the cell membrane where FasL is exposed on the cell surface, shed or secreted. It has been noted before that the proline-rich domain within the cytosolic part of FasL is required for its vesicular association. However, the molecular interactions involved in targeting FasL to secretory lysosomes or to the plasma membrane have not been elucidated. We now identified a family of structurally related proteins that upon co-expression with FasL reallocate the death factor from a membrane to an intracellular localization. Members of this protein family are characterized by a similar domain structure and include FBP17, PACSIN1-3, CD2BP1, CIP4, Rho-GAP C1 and several hypothetical proteins. We show that all tested members of this "FCH/SH3-family" co-precipitate FasL from transfectants. The interactions strictly depend on functional SH3 domains within the FCH/SH3 proteins. Since co-expression of FasL with individual FCH/SH3 proteins dramatically alters the intracellular localization of FasL especially in non-hematopoietic cells, our data suggest that FCH/SH3 proteins might play an important role for the subcellular distribution and lysosomal association of FasL.

Animals↗
PubMed2005

Activation of V gamma 9V delta 2 T cells by NKG2D.

Human Vgamma9 Vdelta2 T cells recognize phosphorylated nonpeptide Ags (so called phosphoantigens), certain tumor cells, and cells treated with aminobisphosphonates. NKG2D, an activating receptor for NK cells, has been described as a potent costimulatory receptor in the Ag-specific activation of gammadelta and CD8 T cells. This study provides evidence that Vgamma9 Vdelta2 T cells may also be directly activated by NKG2D. Culture of PBMC with immobilized NKG2D-specific mAb or NKG2D ligand MHC class I related protein A (MICA) induces the up-regulation of CD69 and CD25 in NK and Vgamma9 Vdelta2 but not in CD8 T cells. Furthermore, NKG2D triggers the production of TNF-alpha but not of IFN-gamma, as well as the release of cytolytic granules by Vgamma9 Vdelta2 T cells. Purified Vgamma9 Vdelta2 T cells kill MICA-transfected RMA mouse cells but not control cells. Finally, DAP10, which mediates NKG2D signaling in human NK cells, was detected in resting and activated Vgamma9 Vdelta2 T cells. These remarkable similarities in NKG2D function in NK and Vgamma9 Vdelta2 T cells may open new perspectives for Vgamma9 Vdelta2 T cell-based immunotherapy, e.g., by Ag-independent killing of NKG2D ligand-expressing tumors.

Animals↗
PubMed2005

Epithelial defence by gamma delta T cells.

Gamma delta T cells constitute a separate lineage of T lymphocytes which differ from conventional alpha beta T cells with regard to T cell receptor (TCR) repertoire and tissue localization. In murine skin, gamma delta T cells expressing a canonical V gamma5 TCR are abundant and contribute as so-called dendritic epidermal T cells to local immune surveillance. In humans, major subsets of gammadelta T cells are recognized on the basis of their TCR V delta usage. While V delta2 cells dominate in the peripheral blood, V delta1 cells are preferentially localized in mucosal tissue including the intestinal epithelia. In this article we summarize basic features of intraepithelial gamma delta T cells and discuss their possible role in epithelial defence.

Animals↗